OBJECTIVE: To determine the effect of highly active antiretroviral therapy (HAART) on the risk of tuberculosis (TB) among persons infected with the human immunodeficiency virus (HIV), and to examine trends in TB. METHODS: For the risk factor analysis, we examined data from the Adult/Adolescent Spectrum of HN Disease (ASD) project from January 1996 through June 1998. ASD is an observational cohort study conducted in over 100 clinics and hospitals in 11 US cities. Poisson regression was used to model the incidence of TB while controlling for HIV-exposure mode, race, country of birth, CD4 count, TB preventive therapy, and half-year of diagnosis. We also examined trends in TB incidence January 1992 to June 1998. RESULTS: During the risk factor analysis period, 80 cases of TB occurred in 16 032 person-years (5.0 cases/ 1000 person-years). In multivariate analysis, the risk of TB was much lower among persons prescribed HAART (RR = 0.2, 95% CI 0.1-0.5, P< 0.001), and also lower among persons prescribed other antiretroviral therapy (RR = 0.6, 95% CI 0.4-1.0, P = 0.05), than the risk in persons not prescribed antiretroviral therapy In addition, TB rates declined from January 1992 to June 1998 (P < 0.001). CONCLUSION: Widespread use of HAART reduced the risk for TB and may help bring about further declines in TB among persons infected with HIV.