A Taliban suicide bomber on a motorbike rammed an Afghan-NATO patrol in the town of Khost on Wednesday, killing 21 people, including three US soldiers, officials said.
Another 37 people were wounded in the blast in the eastern town close to the border with Pakistan, where Taliban and other Islamist insurgents fighting US-led troops have strongholds, hospital officials said.
It was the second major attack on NATO in Khost in three weeks. The government blamed the Taliban and a spokesman for the insurgent militia later claimed responsibility for the attack.
The bombing will only heighten fears about security as NATO prepares to hand responsibility to Afghan forces and recall the vast majority of its 130,000 combat troops by the end of 2014.
The Taliban, leading a 10-year insurgency against the Western-backed government, have begun their annual fighting season with a series of attacks that forced US Defense Secretary Leon Panetta to admit that violence was rising.
Interior ministry spokesman Sediq Sediqqi said Wednesday's blast targeted a combined Afghan and coalition patrol passing through Khost, one of the most troubled parts of Afghanistan.
Khost shares a porous border with Pakistan's tribal belt, which lies outside government control, and where US officials say the Taliban and Al-Qaeda have carved out bases for operations in Afghanistan.
The Haqqani network, a militant group close to Al-Qaeda and blamed for some of the most daring insurgent attacks in Afghanistan, is particularly active in the province.
A US official said three American soldiers were killed and several others wounded in the suicide attack. The embassy in Kabul said an Afghan interpreter was also among the dead.
Amir Padsha, the director of Khost city hospital, said the bodies of three police officers and eight civilians, along with 17 wounded were brought in.
Babri Gul, the head of the Babri Gul private hospital in Khost, said he had received six bodies, including four members of the same family, and 20 wounded.
Afghan police and interior ministry officials confirmed that the four dead announced by the Americans were in addition to the 17 Afghan bodies taken to local hospitals.
A Taliban spokesman told AFP by telephone that one of its fighters blew himself up alongside a US military patrol in Khost, killing 10 American soldiers, including a translator, and four Afghan policemen.
The militia are known to exaggerate their claims and did not speak about civilian deaths.
In Khost on June 1, a suicide truck bomber targeted a US-run base in an incident that killed up to 15 people. US media reported that more than 100 American troops were treated for injuries after that blast.
For the past five years the number of civilians killed in the war has risen steadily, reaching a record 3,021 in 2011 -- the vast majority caused by insurgents, according to UN figures.
The US-led NATO force is also responsible for hundreds of civilian casualties every year, mostly in air strikes aimed at insurgents in Afghan villages.
In southern Afghanistan, a roadside bomb killed at least six civilians, including women and children travelling on a tractor in Puli Alam, the capital of Logar province, deputy provincial police chief Rahis Khan Sadiq told AFP.
On Tuesday, Taliban suicide attackers struck two Afghan-NATO facilities in the southern province of Kandahar -- the birthplace of the extremist movement and the heartland of its insurgency.
The Taliban have waged a bloody fight against Karzai's administration since they were ousted from power in a US-led invasion in 2001.