Two US service members were among those killed in a fiery explosion at a market in the northern Syria town of Manjib, the US military officials said.
Prior to Wednesday's attack, only two US service members had been killed in action in Syria since the start of the campaign in 2014.
Two US service members -- one Department of Defense (DoD) civilian and one contractor supporting the DoD were killed -- and three service members injured while conducting a local engagement in Manjib, the US Central Command (CENTCOM) said.
Initial reports indicate an explosion caused the casualties, and the incident is under investigation, it said.
In accordance with DoD's policy, the names of the service members are being withheld until 24 hours after notification of next of kin is complete, CENTCOM said.
"US service members were killed during an explosion while conducting a routine patrol in Syria today. We are still gathering information and will share additional details at a later time," according to a tweet from the spokesperson for the Operation Inherent Resolve.
ISIS has claimed responsibility for the deadly explosion.
According to the Syrian Observatory for Human Rights monitoring group, at least 15 people, including a US serviceman, were killed in the rare attack in Manbij. It said the cause of the explosion was a suicide bomb outside a restaurant.
"The President (Donald Trump) has been fully briefed and we will continue to monitor the ongoing situation in Syria," White House Press Secretary Sarah Sanders said.
The explosion took place in a market wedged along a crowded street thick with cars. Video that Hawar identifies as from the scene shows people gathered on a crowded sidewalk when the fiery blast occurs.
The attack comes less than a month after Trump announced that US troops would withdraw from Syria.
Trump at that time declared in a video released on Twitter: "We have won against ISIS. We've beaten them and we've beaten them badly. We've taken back the land and now it's time for our troops to come back home."
Condemning the attack, Vice President Mike Pence said, "President Trump and I condemn the terrorist attack in Syria that claimed American lives and our hearts are with the loved ones of the fallen. We honor their memory and we will never forget their service and sacrifice."
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