Serum inoculation of gilts with on-farm isolates is used to protect endemically infected sow herds against reproductive PRRS. However, outbreaks still occur in which the offending virus is genetically similar to the inoculation virus across the entire genome, raising the possibility that “homologous” protection is not complete. Here, we showed that prebreeding gilts inoculated with a virulent virus and challenged in late gestation had incomplete immune protection against challenge with the identical (homologous), immunizing virus as well as a 98% similar heterologous virus. Late gestation challenge resulted in 15% abortions of challenged sows in both groups. Approximately 55% of conceived pigs were weaned in each test group, and viremic pigs at weaning were identified at a rate of 27% in heterologous challenge and 10% in homologous challenge, with at least 1 viremic pig in every litter (n=14, homologous; n=15, heterologous). In contrast, 100% of piglets born to uninoculated, challenged gilts were viremic and failed to thrive. We conclude that live virus inoculation provides immunological protection against reproductive PRRS, but protection is not complete, even against homologous challenge.