Porcine respiratory and reproductive syndrome (PRRS) is an economically important disease of pigs worldwide. Currently used PRRSV vaccines provide incomplete protection. Recently, we identified Mycobacterium tuberculosis whole cell lysate (Mtb WCL) as a potent mucosal adjuvant to modified live PRRSV vaccine (PRRS-MLV). In this study, pigs were unvaccinated or vaccinated with PRRS-MLV plus Mtb WCL, intranasally, and challenged with either homologous (strain VR2332) or virulent heterologous (strain MN184) PRRSV; subsequently, euthanized at three time points post-challenge to evaluate lung immune responses. Microscopic examination of lung sections revealed reduced disruption of the lung architecture and less of interstitial pneumonia in vaccinated, compared to unvaccinated MN184 challenged pigs. The restimulated lung and peripheral blood mononuclear cells revealed increased proliferation of CD8(+) lymphocytes, and in the lung homogenate increased secretion of nitric oxide was detected in vaccinated MN184 challenged pigs. In summary, the adjuvant effects of Mtb WCL to PRRS-MLV resulted in favorable anti-PRRSV immune microenvironment in the lungs to help better viral clearance.