A U.S. official who declined to be named said four U.S. troops had been killed and three wounded in the blast, which an Islamic State-affiliated site said was the work of a suicide bomber. Others said only two had been killed.
The U.S.-led coalition fighting the Islamist militant group said that "U.S. service members were killed during an explosion while conducting a routine patrol", and that it was still gathering details.
The attack, which took place in the town of Manbij, controlled by rebels opposed to Syrian President Bashar al-Assad, appears to be the deadliest on U.S. forces in Syria since they deployed on the ground there in 2015.
Last month, U.S. President Donald Trump made a surprise announcement that he would withdraw all 2,000 U.S. troops from Syria after concluding that Islamic State had been defeated there.
The announcement helped trigger the resignation of his defense secretary, Jim Mattis, stunned allies and raised fears of a long-threatened Turkish military offensive against U.S.-backed Kurdish forces in northern Syria.
A witness in the city said the attack had targeted a restaurant where U.S. personnel were meeting members of the local militia that Washington backs there.
Islamic State later put out a statement saying a Syrian fighter had detonated his explosive vest on a foreign patrol in Manbij.
Two witnesses described the blast to Reuters.
"An explosion hit near a restaurant, targeting the Americans, and there were some forces from the Manbij Military Council with them," one said.
The Manbij Military Council militia has controlled the town since U.S.-backed Kurdish-led forces took it from Islamic State in 2016. It is located near areas held by Russian-backed Syrian government forces and by anti-Assad fighters backed by Turkey.
One of the witnesses said there was a "heavy" presence of military aircraft over Manbij following the blast, which took place near a vegetable market.
Photographs on a local Kurdish news site, which Reuters could not verify, showed two mutilated bodies, several other bodies lying on the ground with people gathered around them, damage to a building and vehicles, and blood smears on a wall.
It was unclear whether the attack might influence Trump’s decision to give more time for the U.S. withdrawal, a conflict he has tired of and described as “sand and death”. (Reporting By Angus McDowall and Ellen Francis in Beirut, Sarah Dadouch in Istanbul and Phil Stewart in Washington; Editing by Kevin Liffey)