Multidrug resistance has become an increasingly important problem in the control and prevention of tuberculosis in large urban centers. Although several small outbreaks of multidrug-resistant (MDR) tuberculosis in New York City have been reported, the increase in the number of cases is not fully explained by these recognized outbreaks, and the modes of transmission have not been clearly delineated. Transmission patterns of MDR tuberculosis in New York City, therefore, were studied by stratifying Mycobacterium tuberculosis isolates from 167 newly diagnosed tuberculosis patients according to their DNA restriction fragment length polymorphisms (RFLP). Forty-three (34%) of 127 drug-susceptible isolates and 19 (79%) of 24 multidrug-resistant isolates had RFLP patterns representing possible recent exogenous infection (primary tuberculosis). Patients who had such isolates were more likely to be seropositive for human immunodeficiency virus (58%; p < 0.05), non-Hispanic black (56%; p < 0.005), U.S.-born (57%; p < 0.001), and have MDR tuberculosis (79%; p < 0.0005). In a logistic regression model, primary tuberculosis remained significantly associated with MDR tuberculosis and black race. In contrast to previous reports, in New York City recent exogenous transmission accounts for most new cases of multidrug-resistant tuberculosis.