Murine hepatitis virus strain 3 (MHV-3) produces a host-strain-dependent spectrum of disease. The development of liver necrosis has been shown to be related to production of a unique macrophage procoagulant activity (PCA), encoded by the gene fgl-2, in susceptible mice. These studies were designed to examine the influence of Thl/Th2 cells on resistance/susceptibility and production of macrophage procagulant activity (PCA) in resistant (A/J) and susceptible (Balb/cJ) strains of mice following infection with MHV-3. Immunization of A/J mice with MHV-3induced a Thl cellular immune response and one Thl cell line (3E9.1) protected susceptible mice and inhibited production of PCA by macrophages both in vitro and in vivo. In contrast, immunization of Balb/cJ mice with an attenuated variant of MHV-3 derived from passaging MHV-3 in YAC-1 cells resulted in a Th2 response. Transfer of spleen cells and T cell lines from immunized Balb/cJ mice failed to protect naive susceptible syngeneic mice from infection with MHV-3 and augmented production of IL-Iβ, TNF-α and PC A by macrophages to MHV-3 in vitro. Serum from immunized Balb/cJ mice contained high titered neutralizing antibody which protected naive Balb/cJ animals from lethal primary MHV-3 infection. These results demonstrate that susceptible Balb/cJ mice generate a Th2 response following MHV-3 infection and that these Th2 cells neither inhibit MHV-3-induced macrophage PC A production nor protect naive mice from MHV-3 infection. The results suggest that antibody protects against primary infection, but could not eradicate ongoing infection. Ribavirin, a synthetic guanosine analogue prolonged survival to MHV-3 infection, inhibited production and transcription of the macrophage pro-inflammatory cytokines IL-1β and TNF-α and Th2 cytokines while preserving Th1 cytokine production. Thus, this data defines the differential role of Th1/Th2 lymphocytes in primary and secondary MHV-3 infection and further defines the importance of macrophage inflammatory mediators in the pathogenesis of MHV-3 infection.