Worldwide, the case-fatality rate of smear-positive pulmonary tuberculosis among persons on treatment is 3.8%. We assessed the case-fatality rate among such patients in Baltimore between January 1993 and June 1998. Tuberculosis incidence was < 17/100 000 population, and 99% of patients received directly observed therapy. Of 174 patients, 42 (24%) died on treatment. Patients who died were older (mean age 62 vs. 47 years; P < 0.001) and were more likely to have underlying medical conditions. In multivariate analyses, older age, diabetes mellitus, and renal failure were independently associated with an increased risk of death. With effective control, tuberculosis may become concentrated in older persons with chronic diseases and be associated with high case-fatality rates. In such settings, acceptable treatment success rates may need to be revised.