This study reports the effect of IFNγ on the replication of porcine reproductive and respiratory syndrome virus (PRRSV) in macrophages. Pretreatment with IFNγ profoundly affected PRRSV replication in porcine macrophages evaluated by reduction in titer and percentage of positive cells. The effect of IFNγ on PRRSV replication was both dose-dependent and related to the time of exposure. The mechanism of action was not due to blocking virus attachment. The inhibitory effect on PRRSV replication in macrophages suggests that IFNγ may play an important role in protection.