Between 1990 and 1994, we conducted a prospective study in five methadone maintenance clinics in San Francisco to determine the rate of tuberculosis (TB) in injection drug users, including those who were anergic. Of the 1,745 persons seen in the clinics, 1,109 completed an evaluation that included skin testing with tuberculin and at least two other antigens (mumps, tetanus, and/or Candida), as well as HIV testing. All persons with a positive tuberculin skin test (TST) and anergic individuals who had radiographic evidence of tuberculous infection (i.e., calcified granulomas) were offered isoniazid (INH) preventive therapy. The median follow-up was 22.0 mo. There were 338 (30.5%) human immunodeficiency virus (HIV)-seropositive patients and 771 (69.5%) HIV-seronegative patients; 96 (28.0%) and 336 (44.0%), respectively, had positive TSTs. Of the HIV-seropositive subjects, 108 (31.9%) had no reaction to any of the three antigens, and were therefore classified as anergic. The rate of TB among the HIV-seropositive, TST-positive patients who did not take INH preventive therapy was 5.0 per 100 person-yr, compared with 0.4 per 100 person-yr among the HIV-seronegative, TST-positive patients (p = 0.007). There were no cases of TB among the anergic subjects. These data indicate that INH preventive therapy is not routinely indicated in anergic, HIV-seropostive patients.