The U.S. -led coalition said in a statement that an F-15E Strike Eagle jet destroyed the Shaheed-129 drone around 12:30 am (2130 GMT) northeast of the al-Tanaf garrison, which is close to the Jordanian border.
"The Syrian regime ... needs to understand that we will keep the right of self-defense of coalition forces aligned against ISIS", he said.
The Syrian Democratic Forces (SDF), which include Arab and Kurdish fighters and are supported with air strikes by a US -led coalition, began an offensive two weeks ago to seize the northern city from Islamic State, which overran it in 2014.
Russia, Syria's staunch ally, said on Monday it would treat USA -led coalition aircraft flying west of the River Euphrates in Syria as potential targets and track them with missile systems and military aircraft, but stopped short of saying it would shoot them down. The ministry also said that Russian Federation was discontinuing cooperation with the USA military as part of the memorandum on preventing mid-air incidents and ensuring flights safety during operations in Syria.
The incident comes amid rising tensions between coalition forces and the regime of Syrian President Bashar al-Assad, which is backed by Russian Federation and Iran.
Russia, a key ally of the Syrian regime, accused the US-led coalition of "complicity with terrorism" after the drone was downed in southern Syria.
The incident follows Sunday's downing of a Syrian SU-22, a Russian-made attack jet.
The U.S. -led coalition's actions were further complicated by Iran, which over the weekend launched strikes on ISIS targets in Eastern Syria - Iran's first missile strikes into the country.
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The US has about 1,000 military personnel in northern Syria, where it has been supplying and supporting partnered forces in their fight in the ISIS-stronghold of Raqqa.
Despite the increasing number of incidents, analysts say neither Syria s regime nor Washington now wants a major confrontation.
He did not specify, though, whether contacts between the United States and Russian forces are maintained through a channel established in accordance with the memorandum on preventing mid-air incidents and ensuring flights safety. The SDF has been armed and trained to fight ISIS.
A statement by the army of Syrian President Bashar al-Assad said the US "atack was an attempt to undermine efforts of the army as the only effective force capable with its allies ... in fighting terrorism across its territory..."
Ford also said that the U.S. would not defend the Kurdish forces it has been supporting so far in case the Kurds engaged in clashes with the Syrian forces.
"We are very well prepared and positioned to defend ourselves", Operation Inherent Resolve spokesman Army Col. Ryan Dillon said earlier this month.
"This was a precautionary measure to allow the coalition to assess the operational risk", a department statement said on Thursday.
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