The flare-up lasted into the small hours of Thursday and was sparked by an attack on positions held by the Kurdish-led Syrian Democratic Forces (SDF) in Deir Ezzor province.
The clash came against a backdrop of escalating tensions between Washington and Damascus over an uptick in the suspected use of chemical weapons by the regime and allied militia.
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"The coalition conducted strikes against attacking forces to repel the act of aggression," it said.
"We estimate more than 100 Syrian pro-regime forces were killed while engaging SDF and coalition forces," while one SDF member was wounded, a US military official said on condition of anonymity.
The SDF and the coalition targeted the attacking forces with air and artillery strikes after "20 to 30 artillery and tank rounds landed within 500 metres (yards) of the SDF headquarters location," the official said.
According to the Syrian Observatory for Human Rights, which only confirmed 20 dead among regime and allied forces, the initial attack took place near Khasham.
The town lies along the Euphrates river, southeast of the provincial capital of Deir Ezzor.
"Regime forces struck SDF positions in several villages and an oil field with artillery fire," Rami Abdel Rahman, the head of the Britain-based monitoring group, said.
"The SDF responded with artillery fire on regime positions in the town of Khasham before the intervention of coalition forces," he said.
Regime and SDF fighters were involved in several skirmishes in the area last year, as they each conducted parallel operations against some of the Islamic State jihadist group's last bastions.
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