Eukaryotic viperins originated from a clade of bacterial and archaeal proteins that catalyse the production of antiviral molecules. Viperin is an interferon-induced cellular protein that is conserved in animals(1). It has previously been shown to inhibit the replication of multiple viruses by producing the ribonucleotide 3 '-deoxy-3 ',4 '-didehydro (ddh)-cytidine triphosphate (ddhCTP), which acts as a chain terminator for viral RNA polymerase(2). Here we show that eukaryotic viperin originated from a clade of bacterial and archaeal proteins that protect against phage infection. Prokaryotic viperins produce a set of modified ribonucleotides that include ddhCTP, ddh-guanosine triphosphate (ddhGTP) and ddh-uridine triphosphate (ddhUTP). We further show that prokaryotic viperins protect against T7 phage infection by inhibiting viral polymerase-dependent transcription, suggesting that it has an antiviral mechanism of action similar to that of animal viperin. Our results reveal a class of potential natural antiviral compounds produced by bacterial immune systems.