With military backing from Russian Federation since 2015, President Bashar al-Assad's government has made huge gains against the jihadists and rebels, and now controls nearly two-thirds of the country.
The Americans have conducted patrols in the city, in vehicles, and on foot, to act as a buffer between Turkey and the US -led coalition's Kurdish partners, a group that's been critical to the fight against ISIS but which Ankara classifies as terrorists.
A Syrian war monitor, the Britain-based Syrian Observatory for Human Rights, reported earlier that at least two USA soldiers were killed in the suicide attack outside a restaurant in Manbij. "We've taken back the land and now it's time for our troops to come back home".
The blast hit the downtown area of Manbij, close to an US-led coalition patrol where talk of an American withdrawal from the city had led to heightened tensions.
President Trump has repeatedly declared that his administration has defeated ISIS, including when he announced his unpopular decision to pull USA troops from Syria. Other sources said that only two had been killed.
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Nine civilians and five US-backed fighters were among the dead in the attack on a restaurant in the flashpoint city of Manbij. Manbij, however, is controlled by Kurdish fighters, considered by Ankara to be terrorists.
The security zones should serve as protection for the Syrian Kurds, who fear a Turkish invasion after Trump announced his decision to withdraw all 2,000 USA troops from Syria.
White House spokeswoman Sarah Sanders said President Donald Trump has been briefed on the situation.
A post-blast video also shared on social media shows windows blown out and a section of wall covered in what appeared to be blood.
ISIS claimed responsibility for the attack, which the ISIS-affiliated Amaq agency said was carried out by a suicide bomber with an explosive vest. Pentagon officials said then that initial withdrawals would be limited to equipment and that no troops had yet departed.
The attack appears to be the deadliest on USA forces in Syria since they deployed on the ground in 2015. "Thanks to the courage of our Armed Forces, we have crushed the ISIS caliphate and devastated its capabilities".
The Pentagon Friday confirmed it had begun pulling out some equipment from Syria as part of the pull-out, but that some 2,000 US forces would remain in place until conditions on the ground allowed for them to leave. Support our independent reporting and analysis today by considering a one-time or monthly donation.