Previous results have shown that pigs that were vaccinated (Vac) with a porcine reproductive and respiratory syndrome (PRRS) modified live virus (MLV) had lower PRRS viral load (VL) but higher porcine circovirus 2b (PCV2b) VL following co-infection with PRRSV and PVC2b than non-vaccinated (nonVac) pigs. In this study, we identified differentially expressed genes (DEGs) at 4 and 7 days post infection (dpi) between Vac and nonVac (VacStatus) pigs. Five DEGs were predicted to decrease replication of PRRSV at 7 dpi in Vac pigs, which may relate to the partial protective effect of the vaccine against PRRS. Other DEG at 4 and 7 dpi were predicted to decrease innate immune response in Vac pigs, which may contribute to the higher PCV2b VL in Vac pigs. These DEGs in blood, and their biological functions, can help us understand PRRS vaccination effects on host-response mechanisms to coinfection with PRRSV and PCV2b in nursery pigs.