The recent construction of PRRSV infectious cDNA clones affords the opportunity for structural and functional studies of PRRSV genes. However, the inherent instability of the PRRSV genome, the requirement of cell culture propagation, and poor virus recovery have limited the usefulness of the PRRSV reverse genetics system for in vivo studies. Here, we report a unique strategy of infecting pigs by bypassing the traditional in vitro cell culture step required for in vivo studies. We demonstrate that inoculation of RNA transcripts of a PRRSV infectious cDNA clone directly into the lymph nodes and tonsils of pigs produces active PRRSV infection. The information from this study will have significant implications for the study of the molecular mechanism of PRRSV pathogenesis using the reverse genetics system.