Defeated government troops fled from Mayadeen to a military airport near the main eastern city of Deir Ezzor, the Syrian Observatory for Human Rights said.
"The area east of the city of Deir Ezzor, on the Iraqi border, is now the largest area in the entire country that is out of army control," said the observatory's director, Rami Abdel Rahman.
The rebel Free Syrian Army said in an email to AFP that insurgents had captured an important military base on the edge of Mayadeen.
"The FSA took control of an artillery garrison in the outskirts of Mayadeen, after a siege that lasted more than 20 days," said Fahd al-Masri, a spokesman for the FSA.
The oil and gas-rich province of Deir Ezzor is home to Sunni Muslim tribes whose ties extend across the border into Iraq.
"In that area of Syria there are deep tribal loyalties, and fighters in western Iraq help the rebels fight the regime," Abdel Rahman told AFP.
Despite its battlefield losses, most oil and gas fields in the large desert province remain still under regime control, said the Britain-based observatory, which relies on a network of activists, lawyers and medics on the ground.
Syria's rebels have also overrun vast swathes of territory in northern Syria along the Turkish border and control most border crossings into Iraq and Turkey, cutting off key supply lines for the regime.
In mid-October, rebels seized Maaret al-Numan, a strategic town in the northern province of Idlib, as well as a section of highway, thereby reducing the army's ability to resupply its forces locked in battle for months with the FSA in the commercial capital Aleppo.
More recently, rebel fighters last Sunday captured Base 46, a sprawling army base in northern Syria after weeks of intense fighting with regime forces.
As the rebellion grows bolder, the regime is focusing its territorial ambitions on Damascus, central Syria and Alawite bastions, according to analysts.
The regime's goal is to entrench in key positions, fight off further rebel advances and hold out for an opportune time to negotiate, they say.
Elsewhere today, warplanes carried out several air strikes on the Eastern Ghuta area on the outskirts of Damascus, said the observatory.
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