Only a small sum was in the box at St Patrick's Holywell Church, near the border village of Belcoo, when the theft was discovered on Wednesday.
The officer in charge of the church saw two men inside as he arrived to lock up for the night.
They left and when he checked the collection box the money was gone, parish priest John Finnegan said.
"It is happening regularly with our churches, I suppose we should be taking extra precautions," he said.
Police appealed for anybody with information to contact them.
Inspector Roy Robinson said: "This was a despicable theft and nothing short of an attack on the congregation and the local community.
"This was money given freely by members of the congregation and visitors and aimed to go towards the good work of the church and congregation and instead criminals have taken it to line their own pockets.
"It is a sad reflection on some people that they should stoop so low as to target a church in this way and I am sure that all right-thinking local people will join me in condemning it."
Police are asking if anyone saw strangers in the church between Monday and Wednesday, or noticed anyone paying close attention to the collection box, to contact them.
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