In adult Syrian golden hamsters (Mesocricetus auratus), intraperitoneal or footpad inoculation of the lymphocytic choriomeningitis virus (LCMV) strains, WE or Armstrong (ARM), caused systemic infection and induced serum LCMV-antibody. Hamster and virus strain-dependent lethal disease also occurred. With WE, MHA and PD4 inbred hamsters failed to eliminate infection and died of wasting disease. LSH and CB inbred hamsters resisted lethal WE-disease and cleared infection. LVG hamsters and inbred LHC hamsters were intermediate in WE-susceptibility; some died of wasting, while others survived with little illness. Resistance to lethal WE-disease directly correlated with a delayed-type hypersensitivity (DTH) response to live-virus footpad inoculation. In WE-resistant LSH and CB hamsters, DTH-responses were induced by intraplantar WE-inoculation; footpad edema began by 5 days, reached maximum thickness by 7 to 9 days, and subsided thereafter. In the other hamster strains, DTH to WE could not be elicited. Unlike WE, ARM was hamster-avirulent; infections were self-limited and did not induce DTH. All survivors of primary LCMV (WE or ARM)-infection resisted secondary WE-challenge, and did not develop DTH to LCMV. Immunosuppressive treatments, abrogating DTH and antibody responses to LCMV, rendered all hamsters susceptible to lethal WE-infection. Hamster DTH most likely mediated resistance to virulent LCMV-infection.