Three service members were killed and three wounded when an improvised explosive device detonated on Tuesday near the central Afghan city of Ghazni, the Nato-led Resolute Support mission said in a statement.
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A US civilian contractor was also wounded in the blast and was receiving treatment with the other wounded, the statement said, giving no further details.
The deaths are the latest in a growing toll on US forces in following the death of an army ranger following an operation against al-Qaida militants in Nimruz province on Saturday. Resolute Support said the soldier had been accidentally shot by a member of Afghan partner forces.
There was no word on the circumstances of the blast on Tuesday but Ghazni has been one of the most heavily fought over areas of Afghanistan this year.
The city was overrun by a large Taliban force earlier this year before being driven off by Afghan and US forces after days of heavy fighting.
Mohammad Arif Noori, a spokesman for the provincial governor, said an armoured vehicle carrying US troops hit a large roadside bomb in the Shahbaz area, just outside the city.
He said US special forces had been conducting operations with Afghan forces around Ghazni city since Monday.
At least 11 US service members have now died in Afghanistan this year, in combat or in so-called “insider attacks” by Afghan soldiers or police.
Four Czech soldiers, serving with Resolute Support, have also been killed.
Ghazni has been one of the most heavily fought over regions of Afghanistan this year and many areas close to the city are in the hands of the Taliban.
The city, which sits on the main highway linking the capital Kabul with Kandahar in the south, was overrun this year by a large Taliban force before it was driven off by Afghan and US troops after days of heavy fighting.
About 14,000 US troops remain in Afghanistan as part of Resolute Support and a separate counter-terrorism mission aimed against militant groups such as al-Qaida and Isis.