Deir Ezzor, North-East of capital Damascus, experienced the rise of Islamic State in 2014.
3000 Christians are estimated to have lived in Deir Ezzor before the 2011 uprising but many fled.
People have gradually started returning as Syrian troops recapture the city, but it is slow progress as living conditions are desirable with destroyed buildings and temperamental access to electricity and water.
On Saturday the Syriac Orthodox Patriarch of Antioch, Ignatius Aphrem II, led a prayer service in the damaged church, St Mary.
According to AFP, the St Mary church still showed signs of the conflict it its congregation had experienced: "Stones, strips of wire, papers and remnants of rockets were strewn across the church floor, and bright sunlight streamed in from the blown-out windows."
The Patriarch said: "It's an indescribable feeling for us to pray in a nearly-destroyed church, which serves as a consolation for our hearts and a message of hope to the people of the city to come back and take part in building it anew."
One man, Shadi Tuma, chose to remain in Deir Ezzor: "The hard times that Deir Ezzor went through pushed the families to leave, but there was a determination inside of me to stay in this city," he told AFP.
"Deir Ezzor will always have coexistence. Christians will always have a presence here."
Beautiful. Orthodox Christian Syrians celebrate their first holy mass in nearly four years at the Church of Virgin Mary in Syria's Deir Ezzor today, free of ISIS terrorists. pic.twitter.com/NFAOF9p6HJ— Sarah Abdallah (@sahouraxo) 3 February 2018
A Christian worshipper receives communion from the Syriac Orthodox Patriarch of Antioch, Ignatius Aphrem II, during a mass held at the heavily damaged Syriac Orthodox church of St. Mary in Syria's eastern city of Deir Ezzor on February pic.twitter.com/9Eqc5DTEON— Lucifuge Rofocale (@rofoca_lucifuge) 3 February 2018
Stay up to date with the latest news stories from a Christian perspective. Sign up to our daily newsletter and receive more stories like this straight to your inbox every morning.