The major goal of the proposed study was to identify specific genetic mutations in the PRRS virus genome that confer escape from host immune responses during PRRSV infection in vivo. The study used samples from the PRRS Host Genetics Consortium, in which approximately 30% of pigs experimentally infected with PRRSV initially cleared the virus, but had a rebound in viremia by 42 dpi. We did extensive sequence analyses of the nsp2 and ORF2-6 region of PRRSV during the acute and rebound period. The results revealed that there was less than 1% genetic variation within or between pigs during the six-week period following infection. Despite the low level of variation, we were able to detect genetically distinct subpopulations of virus genotypes in acute and rebound periods. Multiple sub-populations of virus co-existed in most pigs, and each pig had it’s own distinct population of viral genotypes. In addition, we identified specific mutations in the viral genome that were under selection. The location and frequency of these mutations indicated they are important in escape from virus neutralizing antibody. The rebound pigs had detectable neutralizing antibody to the inoculum virus, while pigs that did not clear virus had no neutralizing antibody to the inoculum virus. Together, these finding indicate that recurrence of viremia in PRRSV infected pigs is due to immune escape variants. Identification of specific mutations that contribute to immune escape will aid design of more effective vaccines for control of PRRS.