The immune response of swine to vaccination with a live, attenuated PRRSV was assessed in the presence and absence of cytokine adjuvants or cholera toxin (CT) to address the hypothesis that adjuvant danger signals, that is, inflammatory cytokines and bacterial extoxin, stimulate a more robust immune response. Animals received four injections of recombinant porcine IL-1 and IL-6, IL-12 alone, or CT alone within I week of intramuscular administration of a vaccine strain of PRRSV, Ingelvac MLV. Serological and cell-mediated responses were monitored for 42 days after vaccination and for a further 10 days after challenge with the virulent VR2332 strain of PRRSV. First, the principal observation was an enhancing effect of IL-12 on the interferon y response to PRRSV, with a more rapid and heightened PRRSV-specific interferon y ELISPOT response in peripheral blood mononuclear cells. The more rapid and robust development of a cell-mediated immune response, as determined by this assay, suggests that IL-12 may influence the induction of antigen-specific T cell responses. Second, animals that received CT adjuvant displayed a more robust antibody response to GP5, the major envelope glycoprotein. Anti-GP5 titers peaked at 21 days after vaccination at more than twice the level of any other treatment, for which the peak response was at 28 days. Third, there was no evidence of PRRSV immunosuppression of immunity to unrelated antigens, including circovirus. CT is a potent mucosal adjuvant, particularly for antibody responses. It acts in part through the production of IL-1 in macrophages, but its effect was not replaced by combination treatment with IL-1 and IL-6. In sum, the results suggest that cytokine adjuvants, particularly IL-12, and CT have the potential to enhance immune responses to live viral vaccines.