Porcine reproductive and respiratory syndrome (PRRS) is one of the most economically important infectious diseases impacting the swine industry worldwide. Prevention and control of PRRS have been problematic, as vaccination has achieved little success. MYH9 (encoded by the gene MYH9) is an essential cellular factor for PRRS virus (PRRSV) infection. The MYH9 C-terminal domain (designated PRA) interacts with viral glycoprotein 5 (GP5), a major PRRSV envelope protein. In this study, we investigated whether soluble PRA could serve as a novel blocking agent of PRRSV infection. Our data showed that preincubation of PRRSV with PRA inhibited virus infection of susceptible cells in a dose-dependent manner. Notably, PRA also exhibited broad-spectrum ability to inhibit infection with diverse strains of both PRRSV genotype 1 and 2. Analysis of the interaction between PRA and PRRSV GP5 revealed that PRA is able to capture PRRSV virions. In conclusion, our data suggest that PRA could serve as a novel broad-spectrum inhibitor of infection by heterogeneous PRRSV strains in vivo.