The sad landmark was reached when a Royal Marine from 40 Commando died from his wounds in the Queen Elizabeth Hospital in Birmingham yesterday morning.
He was injured in a blast in the Sangin district of Helmand Province in southern Afghanistan eight days earlier, the Ministry of Defence said.
Major Renny Bulmer, spokesman for 40 Commando, based in Taunton, Somerset, said: "Our thoughts are with his immediate family who were with him at the hospital.
"His courage and sacrifice will not be forgotten. We will remember him."
He was the 55th UK fatality this year and the seventh member of 40 Commando killed since the Royal Marines took command of the notoriously violent Sangin area in April.
Mr Cameron led tributes to the sacrifices made by the 300 British servicemen and women who have died since operations in Afghanistan began in October 2001.
He said: "It is desperately sad news. Another family with such grief and pain and loss.
"Of course the 300th death is no more or less tragic than the 299 that came before.
"But it is a moment, I think, for the whole country to reflect on the incredible service and sacrifice and dedication that our armed services give on our behalf.
"We are paying a high price for keeping our country safe, for making our world a safer place, and we should keep asking why we are there and how long we must be there.
"The truth is that we are there because the Afghans are not yet ready to keep their own country safe and to keep terrorists and terrorist training camps out of their country. That's why we have to be there.
"But as soon as they are able to take care and take security for their own country, that is when we can leave."
The UK currently has about 10,000 troops in Afghanistan, of whom 8,000 are based in Helmand, the country's most dangerous province.
Since becoming Prime Minister, Mr Cameron has stressed that British forces will not remain in Afghanistan "a day longer than is necessary".
Senior military spokesman Major General Gordon Messenger said it was "entirely right" that people were asking why the UK was involved in the troubled country.
"I would think it wrong if we were not, given the sacrifices that the UK and many other nations are making," he told Sky News.
Defence Secretary Dr Liam Fox said British forces in Afghanistan were protecting the UK's national security.
"Their efforts will bring security and stability to Afghanistan and prevent it from once again becoming a base from which terrorists can attack the UK and our allies around the world," he said.
"The last nine years have seen British forces at the forefront of the campaign, for the last five working hard in one of the most challenging areas of the country, building Afghan capacity to secure and govern their own country - a process which ultimately will allow us to bring our forces home.
"Our Armed Forces are the best in the world, operating daily in the most dangerous and demanding conditions. Some have made the ultimate sacrifice to ensure this essential mission succeeds.
"My thoughts and those of the nation's are with the families and friends of all those servicemen and women who have fallen but our resolve and determination to see the mission through remains steadfast."
The Chief of the Defence Staff, Air Chief Marshal Sir Jock Stirrup, said the Armed Forces took "enormous pride" in their role in the Nato-led mission.
"They put their lives on the line to make the progress we have seen, and will continue to see, in Helmand and across all of Afghanistan," he said.
Shadow defence secretary Bob Ainsworth said Britain could not withdraw until it was sure Afghanistan would never again become a haven for terrorists.
There was further bad news for the Nato coalition today after a military helicopter crashed during an early morning operation in southern Afghanistan, killing three Australian troops and one American.
At least 59 members of international forces have already died in the conflict this month, including 11 Britons.
Video: Death toll reaches 300
Opponents of the war repeated calls for UK troops to be brought home.
Lindsey German, convenor of the Stop the War Coalition, said: "It is no surprise that there is an escalating death rate, among British and other Nato troops as well as Afghans, so this day should be one for reflection for our Government.
"Instead of intensifying the war, the Government should admit it cannot win. This war is unpopular with Afghan people as well as the British public."
The anti-war group will demand the withdrawal of UK forces from Afghanistan in a protest outside Downing Street tomorrow to coincide with Chancellor George Osborne's emergency Budget.
The Royal Marine who died yesterday is expected to be named tomorrow.
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