The purpose of this study was to compare the frequency of infections due to drug resistant Mycobacterium tuberculosis between homeless and nonhomeless populations in an urban community hospital. We retrospectively examined the mycobacteriology registry of this hospital for culture-proven, susceptibility-tested cases of M tuberculosis disease from 1982 to 1987. Clinical records were analyzed for age, ethnicity, sex, residence, and history of alcoholism, intravenous drug abuse, acquired immunodeficiency syndrome, or previous tuberculosis. Of a total of 132 cases, 53 patients were homeless and 79 were not. Drug resistance was found in 21% of the isolates from homeless individuals and 8% of those from nonhomeless persons. Resistance to isoniazid was found in 19% and 1% (p less than 0.01), and for two or more drugs in 15% and 0% (p, 0.01), respectively. Forty-two patients were black, and among them, resistance to one or more drugs was 26.2%, versus 6.6% in nonblacks (p less than 0.01). Ten of 24 homeless blacks had resistant organisms, as opposed to 1 of 18 nonhomeless blacks (p less than 0.05). No other significant differences were noted for the other variables. To our knowledge, this is the first comparison of drug-resistant tuberculosis between homeless and nonhomeless patients using an internal control group. Forty percent of isolates from homeless blacks were resistant, two thirds to both isonlazid and rifampin. These findings support the use of an initial four-drug regimen to treat tuberculosis in this specific population.