We have evaluated the cross-protection of a modified-live virus (MLV) vaccine based on porcine reproductive and respiratory syndrome virus (PRRSV)-2, against a heterologous PRRSV-1 challenge in late term pregnancy gilts. Gilts were vaccinated 42 days prior to breeding and then challenged intranasally with PRRSV-1 at 93 days of gestation. No local or systemic adverse effects related to vaccination were observed in the vaccinated gilts throughout the study. Vaccination resulted in a longer gestation period, a higher number of live-born and weaned piglets, and a significant decrease in the number of stillborn piglets compared to the unvaccinated group. The PRRSV-2 MLV vaccine was also able to significantly reduce PRRSV-1 viremia. At the time of PRRSV-1 challenge, vaccinated gilts had significantly higher PRRSV-1 specific interferon-γ secreting cells but low neutralizing antibody titers against PRRSV-1 compared to unvaccinated gilts. This correlated with a reduction of PRRSV-1 viremia, indicating that cell-mediated rather than humoral immunity played a role in PRRSV-1 clearance from the blood. Fetal thymic tissues from vaccinated pregnant gilts had fewer PRRSV-1 positive cells compared to unvaccinated gilts. Taken together these results indicate that vaccination of gilts with PRRSV-2 MLV vaccine can provide cross-protection against PRRSV-1 challenge and improve reproductive performance.