A car bomb blast killed five Americans, including three U.S. soldiers and a young diplomat, on Saturday, while an American civilian died in a separate attack in the east.
The diplomat, whose name was not given, and other Americans were in a convoy of vehicles in Zabul province when the blast occurred, Secretary of State John Kerry said in a statement.
The soldiers and the diplomat died in the blast along with a civilian employee of the Defense Department and Afghan civilians, Kerry said. His statement gave no overall death toll.
Local and international officials in the region said earlier that six people died in the blast: three U.S. soldiers, two U.S. civilians and an Afghan doctor.
Provincial governor Mohammad Ashraf Nasery was in the convoy, but was unharmed, local and NATO officials said.
"Our American officials and their Afghan colleagues were on their way to donate books to students in a school in Qalat, the province's capital, when they were struck by this despicable attack," Kerry said in his statement.
He said he had met the diplomat during a trip to Kabul, and spoke to her parents after her death. Four other U.S. diplomats were wounded, one critically, Kerry said in his statement.
The convoy was near a hospital and a NATO base at the time of the explosion. Five Afghans, including a student and two reporters, were wounded, a local official said.
The attack came as the top U.S. general, Martin Dempsey, chairman of the Joint Chiefs of Staff, arrived in the country for a short visit to assess how much training Afghan troops need before U.S. troops pull out as planned by the end of 2014.
In an attack in Afghanistan's east, an American civilian working with the U.S. government was killed during an insurgent attack, the NATO-led International Security Assistance Force said in a statement.
Zabul shares borders with Pakistan to the southeast and Kandahar province, the birthplace of the Taliban, to the south.
The Taliban claimed responsibility for the Zabul attack in a text message from spokesman Qari Yousuf Ahmadi. He said a car bomb killed seven foreigners and wounded five others, although he later revised the toll to 13 foreigners killed and nine wounded.
The Taliban routinely exaggerates casualty figures.
The killings followed a bloody Taliban assault in the country's west on Wednesday that killed 44 people in a courtroom in Farah province. The United Nations says civilians are being increasingly targeted.
In a statement posted online earlier on Saturday, Ahmadi said the Taliban would continue to target Afghan judges and prosecutors.
"The Islamic Emirate, from today onwards, will keep a close watch over courthouses, all its personnel and all those who try to harm Mujahideen and will deal with them the same as the judges and prosecutors of Farah."