Objectives.-To determine the incidence of active tuberculosis in human immunodeficiency virus (HIV)-seropositive and HIV-seronegative drug injectors with cutaneous anergy and to examine the effectiveness of isoniazid chemoprophylaxis in preventing tuberculosis among drug injectors with positive tuberculin test results. Design and Setting.-Prospective observational study linked to an ongoing study of HIV infection within a New York City (NY) methadone program; subjects also underwent routine intradermal tuberculin testing and multiple-antigen delayed-type hypersensitivity skin testing. The 31 -month study period ended December 31, 1990. Methods.-Anergic subjects and tuberculin reactors who were HIV seropositive were compared by HIV disease status and CD4+ T-lymphocyte levels. Tuberculosis incidence was calculated for anergics (none treated with isoniazid) and for treated and untreated tuberculin reactors, by HIV serological status. Results.-Among those seropositive for HIV, anergic subjects had more advanced HIV disease and fewer CD4+ cells (median 0.33 vs 0.56 x 10(9)/L, P<.01) compared with tuberculin reactors, although neither clinical status nor CD4+ cell counts consistently predicted anergy. Five (7.6%) of 68 anergic subjects who were HIV seropositive and none of 52 anergic subjects who were HIV seronegative (n=18) or of unknown (n=34) HIV serological status developed active tuberculosis during the study period (P<.05). The tuberculosis incidence rate among anergic subjects who were HIV seropositive was 6.6 cases per 100 person-years (95% confidence interval [CI], 2.1 to 15.3). Of 25 HIV-seropositive tuberculin reactors who did not receive or complete 12 months of isoniazid prophylaxis, tuberculosis incidence was 9.7 cases per 1 00 person-years (95% CI, 2.6 to 24.7; P=0.56, compared with the rate among anergic HIV seropositives); there were no cases of tuberculosis in 53.4 person-years of follow-up for 27 HIV-seropositive tuberculin reactors who received 12 months of prophylaxis (rate difference between treated and untreated groups, 9.7 cases per 100 person-years, 95% CI, 1.3 to 18.0). Conclusion.-Drug injectors with cutaneous anergy who are seropositive for HIV are at high risk of active tuberculosis, similar to that among untreated HIV-seropositive tuberculin reactors. A decreased incidence of active tuberculosis was seen in HIV-seropositive tuberculin reactors receiving 12 months of isoniazid chemoprophylaxis, compared with untreated or partially treated subjects. These results support the routine use of delayed-type hypersensitivity testing to accompany tuberculin testing for drug injectors with known or suspected HIV infection, and consideration of isoniazid prophylaxis for anergic as well as tuberculin-reactive subjects who are HIV seropositive, in populations with a high prevalence of coexisting HIV and Mycobacterium tuberculosis infection.