Summary: Adult mice infected with LCM virus showed a temporary depression in antibody response to sheep red cells, and fewer antibody-forming cells were present in the spleen. There was also a reduction in antibody response to HSA, and decreased susceptibility to systemic anaphylaxis after immunization with OVA. Infection with either ectromelia or cowpox virus did not lead to immunodepression. Following infection with LCM virus in the neonatal period, mice showed a depressed antibody response to sheep red cells during the first few weeks of life, with recovery to normal responsiveness when they became adult. Mice from carrier colonies, in contrast, had normal immune responses whether immature or adult. Ectromelia virus was much more lethal for mice that had been infected a week earlier with LCM virus, and this was attributed to a reduction in the immune response to ectromelia infection. When mice immune to ectromelia were infected with LCM virus and subsequently challenged in the footpad with a large dose of ectromelia virus they survived, but failed to control the growth of virus at the site of challenge. They also showed reduced immune foot swelling compared with control mice, a finding which suggests impaired expression of delayed hypersensitivity. Mice infected neonatally with LCM virus and then 2 weeks later with cowpox virus showed an increase in survival rate, but a decreased footpad response to infection and decreased ability to withstand later challenge with ectromelia virus.