Porcine reproductive and respiratory syndrome (PRRS) has caused heavily economic losses in the swine industry worldwide and current strategies to control PRRS are inadequate. Previous studies have shown that antisense peptide-conjugated phosphorodiamidate morpholino oligomers (PPMO) can be effective antivirals against PRRS virus (PRRSV). PPMO are structurally similar to DNA with modified backbone and resistant to nuclease. In this study, we characterized the combined effect of PPMO. Two pairs of PPMO combinations were identified to show enhanced inhibitory effect on PRRSV replication in cell culture. The PPMO combination also inhibited replication of heterologous PRRSV strains within the same genotype. Treatment of the cells with the combination reduced PRRSV RNA and protein levels. In transiently transfected cells, the PPMO combination suppressed target mRNA expression, indicating that the suppression was due to their antisense effect. These results suggest potential application of these PPMO combinations for the control of PRRSV infection and spread.