An animal model was used to assess whether resistance to superinfection by human immunodeficiency virus (HIV) can exist in vivo. Asymptomatic baboons (Papio cynocephalus), previously infected with HIV-2, were first challenged with homologous virus (HIV-2(UC2) or HIV-2(UC14)) and later with heterologous virus (HlV-2(UC12)). After both virus inoculations, either resistance to vital infection or a transient viremia was observed. The original virus was recovered in 3 baboons, suggesting that reactivation of a latent infection occurred an heterologous challenge and that HIV-2 superinfection is blocked by processes established during prior infection. Antibody titers measured by ELISA and virus neutralization remained at low levels. However, suppression of HIV-1 replication was observed with CD8 T cells and filtered cell culture supernatants. The soluble factor involved was not a β-chemokine. This resistance to HIV superinfection appears to be mediated at least in part by CD8 T cells that suppress virus production.