Syrian troops backed by Russian air power and allied militias opened a new front against rebels around the second city of Aleppo, where Washington said up to 2,000 Iran-backed forces were deployed.
The offensive came as Turkey said it had downed a drone of unknown origin that violated its airspace close to the Syrian border, and a monitor said the death toll in the conflict had risen to more than 250,000.
The Aleppo offensive is the fourth that President Bashar al-Assad's regime has launched since Moscow began an air campaign on September 30.
Control of Aleppo city, once the country's economic hub, has been divided between the regime and rebels since mid-2012. The front lines there and in the surrounding countryside have long been static.
A security source said the operation in southern Aleppo province was backed by Russian strikes and fighters from Iran and Lebanon's Hezbollah militia.
A US official said as many as 2,000 Iranian and Iran-backed forces were aiding the offensive.
The joint command for the Aleppo operation said the army had begun operations on the western and southern outskirts of Aleppo "to liberate you from the armed terrorist groups."
- 'Dozens' of Russian strikes -
The Britain-based Syrian Observatory for Human Rights said the regime had taken control of two villages so far, and that Russian warplanes were pounding two others.
Observatory head Rami Abdel Rahman said Russia had carried out dozens of strikes on the area, which is controlled by a patchwork of rebel groups, including moderates, Islamists and Al-Qaeda affiliate Al-Nusra Front.
A US-designated "terrorist", a member of Al-Nusra, Saudi national Sanafi al-Nasr was killed in an air strike in Aleppo province along with two other senior Al-Nusra members, the Observatory said.
However, it was not clear if the strike was carried out by Russian or US-led warplanes, it said.
The Aleppo fighting comes a day after government forces began an operation north of Homs city, which lies in the centre of the country and is largely under government control.
The Observatory said all but 17 of the 60 people killed in the fighting Thursday were civilians.
Since Syrian forces began ground operations in tandem with Russian air strikes on October 7, their focus has appeared to be a stretch of highway between Aleppo and Homs.
Syrian forces have also sought to reinforce the coastal province of Latakia, a regime stronghold, fighting rebels in the north of the province.
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Moscow says its strikes have targeted the Islamic State group and other "terrorists" but rebels and their backers accuse Russia of targeting moderate and Islamist opposition forces rather than IS.
US President Barack Obama warned Russia Friday they could not "bomb their way" to a peaceful solution in Syria.
- Turkey downs unidentified drone -
Russia's entry into the conflict has raised concerns about military accidents in Syria's crowded air space, where a US-led coalition against IS is also present.
On Friday, Turkey said it had shot down an unidentified drone that had violated its airspace near the Syrian border.
Russia said all its planes in Syria were safe and its drones "working as normal".
But the US military said "all indications" were that the Turks had downed a Russian drone, adding that the Syrian army did not appear to use the same type of aircraft.
Turkey has previously shot down Syrian government helicopters and a plane, and has accused Russia of violating its airspace in recent weeks.
The Syrian conflict began with anti-government protests in March 2011 but has since spiralled into a multi-front civil war involving the regime and its allies, the rival jihadists of IS and Al-Qaeda, and Kurdish militia as well as a string of rebel groups.
The Observatory said on Friday that the death toll was now more than a quarter of a million, over 74,000 of them civilians.
And the UN's humanitarian chief Stephen O'Brien told AFP that the increasing air strikes on the country were putting aid supply routes at risk.
That "has meant that we have been unable to have as many convoys moving to get the supplies to the people in need", he told AFP in an interview.
The US military meanwhile denied claims that Syrian Kurdish forces had got hold of ammunition from a massive air drop that was intended for Syrian Arabs fighting Islamic State jihadists.
The issue is sensitive for the Pentagon, which fears souring relations with Ankara and jeopardising the use of a base at Incirlik in southern Turkey to conduct air raids against IS.
US-led forces parachuted tonnes of small-arms ammunition and rockets on Sunday to rebels fighting IS as part of a new policy to equip vetted rebel leaders.