The association between HIV-2 infection and bacterial pneumonia, sepsis, and pyomyositis was examined in 201 consecutive patients hospitalized at Simao Mendes National Hospital in Bissau, Guinea-Bissau with such bacterial diseases and 201 age- and sex-matched controls drawn from a census in a semi-urban area of Bissau. Among cases, HIV-1 prevalence was 5.4%, HIV-2 prevalence was 27.9%, and combined HIV-1 and HIV-2 prevalence was 6.4%. Among controls, these prevalences were 1.5%, 9.0%, and 1.0%, respectively. The prevalence of HIV-2 infection was 25.0% among cases with pneumonia (n = 140), 38.7% among those with sepsis (n = 31), and 30.0% among those with pyomyositis (n = 30). Among the 93 cases for whom T lymphocytes were determined, the absolute number and percentage of CD4 cells and the CD4/CD8 cell ratios were markedly suppressed in the HIV-2-positive group, especially in those with sepsis. Of the 194 patients available for follow-up, 160 were classified as cured or improved, 10 did not improve, and 24 died. Mortality from sepsis and pyomyositis was significantly greater among HIV-2-infected cases than HIV-negative patients. The median percentage of CD4 cells was significantly lower among HIV-2-positive patients who died (9.0%) than survivors (16.5%). These findings confirm the existence of a significant association between HIV-2 and severe bacterial infections as well as a significantly higher mortality during hospitalization from sepsis and pyomyositis in HIV-2-positive patients compared to HIV-negative patients.