BACKGROUND: Treatment of latent infection is needed to protect HIV‐infected individuals against tuberculosis. A previous report addressed short‐term efficacy of three regimens in HIV‐infected adults. We now report on long‐term efficacy of the study regimens. METHODS: Three daily self‐administered regimens were compared in a randomized placebo‐controlled trial in 2736 purified protein derivative (PPD)‐positive and anergic HIV‐infected adults. PPD‐positive subjects were treated with isoniazid (INH) for 6 months (6H), INH plus rifampicin for 3 months (3HR), INH plus rifampicin and pyrazinamide for 3 months (3HRZ), or placebo for 6 months. Anergic subjects were randomized to 6H or placebo. RESULTS: 6H initially protected against tuberculosis in PPD‐positive individuals; however, benefit was lost within the first year of treatment. Sustained benefit was observed in persons receiving 3HR and 3HRZ. In a Cox regression analysis, the adjusted relative risk for tuberculosis compared with placebo was 0.67 [95% confidence interval (CI), 0.42‐1.07] for 6H, 0.49 (95% CI, 0.29‐0.82) for 3HR, and 0.41 (95% CI, 0.22‐0.76) for 3HRZ. When the rifampicin‐containing regimens were combined, the adjusted relative risk for tuberculosis compared with placebo was 0.46 (95% CI, 0.29‐0.71). Among anergic subjects, a modest degree of protection with 6H was present (adjusted relative risk, 0.61; 95% CI, 0.32‐1.16). Treatment of latent tuberculosis infection had no effect on mortality. CONCLUSION: Six months of INH provided short‐term protection against tuberculosis in PPD‐positive HIV‐infected adults. Three month regimens including INH plus rifampicin or INH, rifampicin and pyrazinamide provided sustained protection for up to 3 years.