A little-known tea party-backed candidate rode to victory in the Republican Senate primary in Delaware, dealing yet another setback to the party establishment in a season of recession and political upheaval.
A second insurgent led for the Republican Senate nomination in New Hampshire.
Republican hopes to capture control of the House of Representatives and possibly the Senate in a tough political climate for Democrats - President Barack Obama's popularity has fallen below 50% - have been complicated by the success of several insurgents backed by the anti-tax tea party movement.
Democrats, who face a wave of voter anger over the sputtering economy, hope the Republicans will be saddled with unelectable candidates whose ultraconservative policies may be too extreme for moderate voters in the November 2 general election when control of both houses of Congress will be at stake.
Republicans must gain 10 seats this autumn if they are to win control of the Senate in November, and their chances count heavily on their ability to prevail in both Delaware and New Hampshire. Tea party-backed candidates earlier won Senate nominations in Nevada, Colorado, Florida, Kentucky and Alaska.
In all, five states chose nominees for the Senate Tuesday, and six more had gubernatorial hopefuls on primary ballots.
Tea party favourite Christine O'Donnell defeated nine-term Mike Castle, a fixture in Delaware politics for a generation and a moderate who campaigned with the strong backing of party officials in his state and in Washington. Nearly complete returns showed her with 53% of the vote.
Democrats rejoiced, as did O'Donnell's supporters.
Castle's defeat boosted the number of members of Congress who have lost primaries to eight, five Republicans and three Democrats. But that list does not include a lengthy list of Republican contenders who fell to tea party-supported challengers despite having the backing of party officials eager to maximise their gains in November.
The Republican primary in Delaware took a sharp turn for the negative three weeks ago after the Tea Party Express, former vice presidential candidate Sarah Palin and Senator. Jim DeMint of South Carolina announced they would come to O'Donnell's aid.
The tea party movement emerged after the election of President Barack Obama as a loose-knit coalition of community groups largely made up of people with conservative and libertarian views who say government has grown too large and spends too much, threatening individual liberties.
The movement's name is taken from the Boston Tea Party, a 1773 protest in which activists in the then-British colonies in America boarded ships and threw their cargo of English tea into Boston Harbor in a symbolic act of protest against taxes imposed by Parliament in London.