Control by genes within H-2 of natural resistance to fully virulent salmonellae in susceptible mice was studied by the typhoid relapse model. Susceptible (Itys), H-2 congenic C57BL/10 (B10) lines were infected with a lethal dose of the virulent S. typhimurium C5 and rescued from death by ampicillin therapy, inducing a chronic infection. The response to therapy and its cessation, both early and late in the infection, varied in different strains. B10 (H-2b) and B10.D2 (H-2d) responded less well to therapy, and were more prone to relapse on its removal, than B10.A (H-2a) or B10.M (H-2f) mice. This haplotype distribution is the same as that previously reported for H-2 linked resistance and susceptibility of similar mice to salmonellae of low virulence. The results indicate that resistance to a virulent salmonella capable of causing natural infection is influenced by genes within the MHC.