The genetic and antigenic stability of porcine reproductive and respiratory syndrome (PRRS) virus during infection in pigs was assessed using field and experimental data. Among field isolates, we found that PRRS virus varied both genetically and antigenically. Even within the same farm, various phenotypic strains of PRRS virus were present simultaneously. Experimentally, we demonstrated that PRRS virus “quasi-species” appeared over time as the virus replicated in animals. Although the degree of genotypic changes in the gene coding for the major envelope protein (i.e., open reading frame 5) was less than expected based on field observations; some mutants appear to have been changed significantly. Overall, our observations suggest that persistence of PRRS virus in pigs may be attributed to viral mutation, although the actual role of viral mutation in persistent PRRS virus infection remains to be determined. The presence of various phenotypic strains within the same farm or herd may account for the apparent ineffectiveness of PRRS control by monovalent vaccine.