It is generally considered that African nonhuman primates (NHPs) do not progress to AIDS. In the wild, due to either a shorter life span or an insufficient follow-up of the animals, no AIDS cases were described to date. However, in captivity, at least one case of immunodeficiency was reported for each of the currently available models of natural infection (African green monkey, sooty mangabey and mandrill). Furthermore, experimental infection of three other African NHP species, the black mangabey (BkM), the chimpanzee and the baboon with heterologous viruses, such as SIVsmm, HIV-1 and HIV-2, respectively also resulted in progression to AIDS. Here, we present the clinical, pathologic and virologic findings of these cases of progressive disease in African NHP hosts. Similar to pathogenic infections of humans and rhesus macaques, progression to AIDS in natural hosts is characterized by: CD4+ T cell depletion in peripheral blood and intestine, opportunistic infections and neoplasia, severe weight loss, lymphocytic interstitial pneumonia, lymphoid tissue hypoplasia, and giant cell disease. Importantly, in these animals the set point levels of viral loads (VLs) were higher than in the majority of naturally-infected African NHPs, with significant increases of VLs occurring in association with disease progression. Finally, African NHP progressors showed increased levels of immune activation and cell proliferation, which differentiate them from the vast majority of African NHPs in which immune activation is not significantly increased during the chronic SIV infection compared to their SIV uninfected counterparts. Despite the rarity of AIDS cases in African NHPs, the spectrum and morphology of the observed lesions are very similar to those encountered in humans or macaques with AIDS. Therefore, we suggest that the “nonpathogenic” models of SIV infection should be reconsidered as “persistently nonprogressive” SIV infections. The fact that SIV-infected African NHPs may, in fact, occasionally progress to AIDS emphasizes the importance of studying these models to better understand AIDS pathogenesis and design new therapeutic and preventative interventions for HIV infection.