Voters in Blaenau Gwent, south Wales, failed to re-elect Labour in one of its former strongholds, then the Tories almost lost Bromley and Chislehurst to the Liberal Democrats, previously safe Conservative territory.
In a further setback for the Prime Minister, Labour was relegated to fourth in Bromley and Chislehurst, behind the UK Independence Party.
Independent candidates won Blaenau Gwent's seats in both the Commons and on the Welsh Assembly, leaving Labour without a majority on the latter.
The Bromley and Chislehurst contest in south-east London was the first major by-election challenge for Mr Cameron as Tory leader.
But the Tories' 13,342 majority over the Lib Dems from last year's General Election was slashed to less than 700.
Labour also saw their support slide as UKIP moved ahead into third place.
The results of the Bromley and Chislehurst contest did nothing to support opinion poll claims that his leadership has revived the party's electoral fortunes.
A YouGov poll for the Daily Telegraph today declares Mr Cameron the public's preferred prime minister over either Mr Blair or his heir-apparent, Chancellor Gordon Brown.
But it was Liberal Democrat leader Sir Menzies Campbell who was given a boost this morning as his candidate came 633 votes short of taking Bromley and Chislehurst from the Tories' Bob Neill, after the Conservatives' vote share slumped 11.11%.
In last year's General Election Tory Eric Forth - whose death prompted yesterday's by-election - was returned with a majority of 13,342.
Sir Menzies said: "This is a stupendous result for the Liberal Democrats in one of the safest Conservative seats in the country.
"It shows that there is no confidence in Cameron's Tories in the Conservative heartlands.
"Together with the results in Wales there has been a complete rejection of the Labour government following upon the Liberal Democrat success in Dunfermline earlier this year.
"Liberal Democrats are now challenging both Labour and the Conservatives, even in their heartlands."
But Mr Neill used his acceptance speech to round on the Lib Dems' campaign tactics: "A minority of candidates, principally the Liberal Democrats, have chosen to fight this campaign with the most vigorous and underhand example of cynical personal abuse that I have encountered in 30 years of politics."
He told the Lib Dems: "If you sometimes wonder why it is that people in this country are turned off by politics, get a mirror and look at yourselves."
Labour's vote in Bromley and Chislehurst slumped 15.57% as it was overtaken by the UKIP's Nigel Farage.
Mr Farage, an MEP, said: "I'm pleased that UKIP came third and beat Labour into fourth place ... it sends a very loud message that it's time Mr Blair went."
At Blaenau Gwent, Labour's Owen Smith was beaten by independent Dai Davies, the agent of former MP Peter Law, who died in April.
However, there was a 4.74% vote share increase for Labour, reducing the independent majority from 9,121 to 2,484 votes.
Mr Law's widow Trish, meanwhile, beat Labour's John Hopkins to the Welsh Assembly seat by more than 4,000 votes.
That result denies Labour a majority on the Assembly.
Labour's failure to regain either seat in the socialist citadel of Blaenau Gwent is another setback for Mr Blair.
Mr Law, who was elected in 2003 as a Labour Assembly Member, won the Commons seat as an independent in last year's General Election after the party imposed an all-women shortlist.
The constituency's new MP, Mr Davies, hailed a "political revolution" in his acceptance speech.
He said: "Political parties take note. You take people for granted at your peril. It's the people that matter, not the political parties.
"The dinosaurs thought they would live for ever - they died out. Political parties take note and listen to the people or you're in trouble."
Mrs Law added: "This is a victory for Blaenau Gwent. This is a victory for honesty and integrity."
She said she wanted to ensure "that never again will the people of this area be taken for granted".
Mr Smith acknowledged Labour had failed to make amends for last year's shortlist fiasco.
"We need to reach out to those people who left the party and try to heal some of the rifts that were here," he told the BBC.
"People have decided that the rift with the Labour Party - that they were not ready to have that rift healed yet."
But Wayne David, Labour MP for Caerphilly, said the defeat was not a reflection on the party's leadership, despite conceding it had taken place against a "not very favourable national backdrop" for Labour in recent weeks.
He said: "Naturally we are very disappointed but I think the important thing for the Labour Party is we fought an excellent campaign and, compared with last year, I think the final result will show we have made progress."
BROMLEY & CHISLEHURST
C hold
Bob Neill (C) 11,621 (40.00%, -11.11%)
Ben Abbotts (LD) 10,988 (37.82%, +17.52%)
Nigel Farage (UKIP) 2,347 (8.08%, +4.88%)
Rachel Reeves (Lab) 1,925 (6.63%, -15.57%)
Ann Garrett (Green) 811 (2.79%, -0.39%)
Paul Winnett (NF) 476 (1.64%)
John Hemming-Clarke (Ind) 442 (1.52%)
Steven Uncles (Eng Dem) 212 (0.73%)
John Cartwright (Loony) 132 (0.45%)
Nick Hadziannis (Ind) 65 (0.22%)
Anne Belsey (Money Reform) 33 (0.11%)
C maj 633 (2.18%)
14.32% swing C to LD
Electorate 71,818; Turnout 29,052 (40.45%, -24.37%)
2005: C maj 13,342 (28.92%) - Turnout 46,137 (64.82%) Forth (C) 23,583 (51.12%); Reeves (Lab) 10,241 (22.20%); Brooks (LD) 9,368 (20.30%); Hooper (UKIP) 1,475 (3.20%); Garrett (Green) 1,470 (3.19%)
BLAENAU GWENT COMMONS CONSTITUENCY
Ind hold
Dai Davies (Ind) 12,543 (46.17%, -12.00%)
Owen Smith (Lab) 10,059 (37.03%, +4.74%)
Steffan Lewis (PC) 1,755 (6.46%, +4.07%)
Amy Kitcher (LD) 1,477 (5.44%, +1.15%)
Margrit Williams (C) 1,013 (3.73%, +1.41%)
Howling Laud Hope (Loony) 318 (1.17%)
Ind maj 2,484 (9.14%)
8.37% swing Ind to Lab
Electorate 52,508; Turnout 27,165 (51.73%, -14.40%)
2005: Ind maj 9,121 (25.87%) - Turnout 35,251 (66.14%) Law (Ind) 20,505 (58.17%); Jones (Lab) 11,384 (32.29%); Thomas (LD) 1,511 (4.29%); Price (PC) 843 (2.39%); Lee (C) 816 (2.31%); Osborne (UKIP) 192 (0.54%)
BLAENAU GWENT ASSEMBLY CONSTITUENCY
Ind hold
Trish Law (Ind) 13,785 (50.33%)
John Hopkins (Lab) 9,321 (34.03%, -36.19%)
Steve Bard (LD) 2,054 (7.50%, -3.36%)
John Price (PC) 1,109 (4.05%, -5.51%)
Jon Burns (C) 816 (2.98%, -2.74%)
John Matthews (Green) 302 (1.10%)
Ind maj 4,464 (16.30%)
Electorate 52,582; Turnout 27,387 (52.08%, +14.73%)
2003: Lab Co-op maj 11,736 (59.36%) - Turnout 19,771 (37.36%) Law (Lab Co-op) 13,884 (70.22%); Bard (LD) 2,148 (10.86%); Elis (PC) 1,889 (9.55%); O'Keefe (C) 1,131 (5.72%); Thomas (UKIP) 719 (3.64%)
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