The transmembrane zinc metalloprotease, ZMPSTE24, works in cooperation with interferon induced transmembrane protein 3 (IFITM3) to restrict entry of several enveloped viruses. We investigated the role of ZMPSTE24 in porcine reproductive and respiratory syndrome virus (PRRSV) replication. ZMPSTE24 overexpression significantly reduced PRRSV replication in MARC-145 cells. Interestingly, knockdown of endogenous ZMPSTE24 did not significantly impact virus replication. There was no significant difference in the percentage of PRRSV positive cells and viral RNA copies at 3 hours post infection (hpi) between cells transfected with ZMPSTE24-FLAG and vector control. Our results suggest that ZMPSTE24 overexpression may restrict PRRSV replication at a post-entry step.