The course of systemic infection with lymphocytic choriomeningitis virus (LCMV) was studied in BALB/cA and C.B-17 mouse strains differing in the immunoglobulin heavy chain region (Igh). Susceptibility to intracerebral infection and the ability to clear the virus differed significantly between these presumably congenic strains, suggesting that a gene in the Igh region might influence the course of this infection. A difference in virus spread prior to appearance of the immune response could not explain the observed differences. On the other hand, the differences in course of infection correlated with a difference in virus-specific T-cell responsiveness measured in terms of virus-specific cytotoxicity in vitro and delayed-type hypersensitivity in vivo. Analysis of F1, BC1 and F2 progeny showed that differential T-cell responsiveness was influenced by a single gene or gene complex; however, no linkage was found between this locus and the Igh-C region. Taken together, these results indicate that an additional, and previously unknown, genetic difference exists between these two mouse strains, and that the involved locus carries a gene which significantly affects T-cell responsiveness to LCMV.