The jihadists took control of Al-Qaryatain in the central province of Homs early today, the Syrian Observatory for Human Rights monitor said.
Violent clashes broke out after the jihadists sneaked in, the Britain-based Observatory's Rami Abdel Rahman said.
Government troops had surrounded the town, where several Christian families are believed to be living, he said.
Al-Qaryatain was home to some 30,000 people before Syria's war broke out in 2011, 900 of them Christians.
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In early August 2015, IS abducted 270 Christians from the town, transporting them around 90 kilometres away deep in the Syria desert and locking them up in an underground dungeon. They were freed 25 days later.
The same month, IS destroyed parts of a monastery in the town and reduced a fifth-century mud brick church to rubble using explosives and bulldozers.
Earlier this week the jihadists launched an assault on government positions in Syria's vast Badiya desert, killing at least 128 regime troops.
Syrian troops pushed through the desert, which separates the main cities of the west from the Euphrates Valley this summer, and broke a years-long IS siege on government enclaves in the eastern city of Deir Ezzor last month.
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