Viperin is an interferon-induced cellular protein conserved in animals1. It was shown to inhibit the replication of multiple viruses by producing a ribonucleotide called 3'-deoxy-3'4'-didehydro-CTP (ddhCTP), which acts as a chain terminator for the viral RNA polymerase2. Here we show that the eukaryotic viperin has originated from a clade of bacterial and archaeal proteins that protect against phage infection. Prokaryotic viperins (pVips) produce a set of modified ribonucleotides that include ddhCTP, as well as ddhGTP and ddhUTP. We further provide evidence that pVips protect against T7 phage infection by inhibiting viral polymerase-dependent transcription, implying an anti-viral mechanism of action similar to the animal viperin. Our results unveil a potential repository of natural antiviral compounds produced by bacterial immune systems.