Context: Human immunodeficiency virus infection is rife in sub-Saharan Africa and in southern Africa in particular. Despite the increasing availability of antiretroviral therapy in this region, opportunistic infections remain common and frequently involve the gastrointestinal tract., Objective: To review the histopathologic findings and distinguishing features of human immunodeficiency virus-associated gastrointestinal infections in southern Africa and relate those findings to the documented international literature., Data Sources: The available literature on this topic was reviewed and supplemented with personal experience in a private histopathology practice in South Africa., Conclusions: In southern Africa, the range of gastrointestinal, opportunistic infectious pathology in human immunodeficiency virus afflicted patients is diverse and includes viral, bacterial, fungal, and parasitic infections. This infectious pathology is sometimes a manifestation of systemic disease. In profoundly immunocompromised patients, unusual histologic features, involvement of uncommon gastrointestinal tract sites, and more than one pathogen may be seen.