There are currently 10,000 UK forces in Afghanistan
About 8,000 British troops based in Helmand province in Afghanistan are to come under the operational command of the US, the Ministry of Defence says.
The move is part of a restructuring of Nato forces, with command and control in southern Afghanistan split into two.
The UK's Maj Gen Nick Carter will now oversee Kandahar, while Maj Gen Richard Mills from the US will take on Helmand.
Meanwhile, a British marine from 40 Commando Royal Marines has been killed in an explosion in Sangin.
The command of the 1,100-strong British battle group based in Sangin - an area which has seen a number of UK deaths recently - and in Kajaki will also come under US-led force from 1 June.
Maj Gen Gordon Messenger - UK troops will see "very little change"
Asked about the changes at a news conference in Berlin, Prime Minister David Cameron said the move "does make good sense in terms of maximising the impact of what both we and the Americans are doing in the southern part of the country, which is absolutely vital".
"British and American troops have been working together in many theatres over many decades and don't have a problem working together," he said.
The changes were announced by Maj Gen Gordon Messenger, who told a news conference in central London that the changes made "complete sense" and were "welcome".
"The span and complexity of the command challenge in southern Afghanistan has increased enormously in recent months and these changes provide the best command support to the troops on the ground," he added.
Jonathan Beale, BBC defence correspondent
This change in command structure for southern Afghanistan makes military sense. Nato commanders agree - with a recent influx of US forces there are now too many troops in too big an area for just one command. There have also been two separate military operations going on in Helmand and Kandahar.
Nor is there any real political controversy over the fact a US two-star general will take charge of British troops in Helmand. In the past they have come under Dutch and Canadian command. General Stanley McChrystal has long stated that he is "nation-blind" when it comes to Nato forces.
That is not to say there are national sensitivities. The British are keen to point out that in future the command of Helmand will rotate between American and British generals.
There may also be controversial changes ahead. Nato commanders have been debating whether there are enough troops in Sangin - where British forces have suffered heavy casualties. Sangin and Kajaki have now been transferred to the control of a US-led force. It raises the question as to whether US troops will reinforce or even eventually replace British troops there.
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