OBJECTIVE: To determine the prevalence and risk factors for human immunodeficiency virus (HIV) and tuberculosis (TB) infection and investigate the relationship between these two infections in homeless adults. DESIGN: Cross-sectional study. SETTING: Inner-city shelters and free meal programs. PARTICIPANTS: A representative sample of 1226 adults (> or = 18 years) were enrolled from community sites. MAIN OUTCOME MEASURES: Serum HIV-1 antibody status and tuberculin skin test reactivity. RESULTS: Human immunodeficiency virus seroprevalence was 8.5% (95% confidence interval [CI], 7.0% to 10.1%) and the prevalence of TB infection was 32% (95% CI, 30% to 37%). Nineteen percent of the HIV-seropositive subjects had positive tuberculin skin tests. Independent risk factors for HIV infection included younger age, black race, male homosexual contact, injection drug use, use of injection drugs in shooting galleries, and selling sex. Tuberculosis infection was associated with the duration of homelessness and living in crowded shelters or single-room-occupancy hotels. Injection drug use, a risk factor for HIV, was also a risk factor for TB, with a particularly strong association in women. No evidence of an association between TB and HIV infection was found, even after accounting for anergy. CONCLUSIONS: The homeless population in the United States should be considered a group at high risk for HIV infection and TB. Given the constellation of risk factors present, the high prevalence of infection, and lack of access to medical services, we anticipate that these communicable diseases in this population will represent a growing public health problem.