Immune responses counteract infections and can also cause collateral damage to hosts. We investigated functional outcomes of variation in the rapidly evolving antiviral double-stranded RNA (dsRNA) sensing factor Oligoadenylate Synthetase 1 (OAS1) in primates as a model for understanding how individual immune pathways evolve to minimize deleterious effects on host fitness. Upon binding of dsRNAs, OAS1 polymerizes ATP into 2′–5′ linked oligoadenylate (2-5A), which in turn activates Latent Ribonuclease (RNase L) to kill virus infected cells. OAS1 can undergo auto-activation by host encoded RNAs, raising the question of how it might evolve to mitigate RNase L-mediated cytotoxicity. Using a new yeast-based growth assay, we observed a pattern of frequent loss of 2-5A synthesis by OAS1 from several species. In gorillas, we identified a polymorphism in a conserved substrate binding residue that severely decreases catalytic function. In contrast, lowered 2-5A generation previously associated with variation in humans results from production of unstable OAS1 isoforms. Examination of OAS1 function in monkeys revealed a spectrum of activities, including the complete loss of 2-5A synthesis in tamarins. Frequent loss of catalytic activity in primates suggests that costs associated with OAS1 activation can be so detrimental to host fitness that its pathogen-protective effects are repeatedly forfeited.