We investigated an outbreak of tuberculosis in a large shelter for the homeless to assess the role of exogenous reinfection as opposed to reactivation of endogenous infection as the cause of secondary tuberculosis in this population. Exogenous reinfection is considered relatively unimportant in the United States and other developed countries. Of 49 shelter-related cases, 22 had cultures resistant to both isoniazid and streptomycin and of the same phage type, indicating recent transmission originating with a single index patient. The probable index patient had a 10-year history of isoniazid and streptomycin resistance--an uncommon pattern at the shelter during the three years preceding the outbreak. In 4 of the 22 cases, the patient had previously had documented tuberculosis infection or disease. These reinfected patients had extensive lung cavitation and numerous acid-fast bacilli on sputum smears--features associated with contagiousness. In contrast, patients with tuberculosis for the first time (primary tuberculosis) are usually less contagious. We conclude that exogenous reinfection may have been an important factor leading to highly contagious secondary cases and an acceleration of the usual pattern of tuberculosis transmission in this highly susceptible population.