A joint force of more than 200 fighters died in a failed attack on the US and Kurdish base, according to a US official and three Russians familiar with the matter.
The US official said the death toll was around 100 with 200 to 300 injured, but could not say how many were Russians.
The assault may have been a rogue operation and Russia’s military said it had nothing to do with the attack – which the US has accepted.
Former Russian diplomat and lawmaker who is now an independent political analyst Vladimir Frolov said: “This is a big scandal and a reason for an acute international crisis.
“But Russia will pretend nothing happened.”
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Russian spokesman Dmitry Peskov would not comment on reports of Russian casualties and said the Kremlin only tracks data on its own armed forces.
Defence Secretary Jim Mattis said it was “perplexing” but did not add further details.
Putin turned the tide of the seven-year war in Syria by committing air and manpower to Assad’s forces in 2015, which stemmed calls for the removal of the Syrian leader.
Now ISIS – who controlled huge sections of Syria – is largely defeated, rival powers and militias are fighting to fill the vacuum.
Russia, Iran, Israel and Turkey have all had aircraft shot down in or near Syria this month.
The death of the Russian mercenaries comes after a US drone destroyed a Russian-made T-72 battle tank in Syria in “self-defence”, according to US Central Command.
On Saturday, US forces destroyed a Russian-made T-72 tank in Syria after pro-Assad forces opened fire on US special ops and Syrian Democratic Forces (SDF).
Colonel Dillon confirmed the news, adding: “The tank had been manoeuvring with coordinated indirect fire on a defensive position occupied by Syrian Democratic Forces and coalition advisers.
“The defensive position was within effective range of the hostile weapons systems. Coalition officials maintained regular contact with Russian counterparts via established deconfliction lines to avoid misperceptions and miscalculations that could endanger each other’s forces.”
US forces have been fighting alongside the SDF for years while Russia has been training and equipping pro-Assad forces in the region.
Russia’s military says it had nothing to do with this attack either – a claim accepted by the US.
The SDF is an alliance of Kurdish and Arab fighters, working with coalition support to root out the final ISIS fighters still in the region.
The main Kurdish component of the SDF, known as People’s Protection Units (YPG), is the target of a military operation in northern Syria by US ally Turkey, which considers the YPG a ‘terrorist’ group.
The attack on the SDF in eastern Syria could spell further trouble for the US-backed forces, which have largely avoided confrontation with pro-Assad units until now.