Superinfection of human immunodeficiency virus (HIV)-1-infected rabbits with Treponema pallidum, Mycobacterium avium, herpes simplex, Candida albicans, Mycoplama incognitus, and malignant catarrhal fever virus, as well as irradiation or cortisone treatment, fails to activate production of infectious virus. For up to 6 months after infection of rabbits with HIV-infected cells or free virus, there are neither clinical symptoms nor positive laboratory tests for detection of HIV. However, after superinfection with other agents, HIV sequences may be transiently found in peripheral blood mononuclear cells by polymerase chain reaction (PCR), and multiple antibodies to HIV antigens may be detected by Western blotting. Both the PCR positivity and Western blot reactivity become negative with time after superinfection. Other than delayed healing of the skin lesions produced by T. pallidum and vaccinia in HIV-infected rabbits, there is no evidence of any immune abnormality. After death, gag sequences are detectable in the splenocytes of essentially every HIV-infected rabbit, and the splenocytes of eight of 25 infected rabbits responded by proliferation to HIV peptides. In addition, gag sequences are detectable in rabbits that are injected with lymphoid cells from HIV-infected rabbits. However, after multiple testing of both peripheral blood of living rabbits and organs of rabbits that died or were killed (spleen, brain, lymph nodes, liver, and gastrointestinal tract), no viable virus has ever been convincingly detected by in vitro cultivation with indicator cells. In contrast to some other published reports, these data indicate that HIV-1 infection of rabbits does not provide a model for AIDS pathogenesis therapy or prevention, but it may be useful as a model to study the relative resistance of a small fraction of the human population to development of AIDS after HIV infection.