We conducted a proportional morbidity study to determine the factors associated with, patterns of, and proportion of cases of tuberculosis with drug resistance in Puerto Rico. We abstracted data from 279 report forms of new cases of tuberculoses reported to the Puerto Rico Health Department between 1987 and 1990 in which isolates had been tested for drug susceptibility. Overall, 55 (19.7%) of the 279 cases of tuberculosis were resistant to at least one drug, and 27 (9.7%) were resistant to more than one drug. Among the 59 patients with previous tuberculosis therapy, 20 (33.9%) had isolates that were drug-resistant. Among the 220 without previous therapy, 35 (15.9%) had isolates that were drug-resistant. For all 279, resistance to isoniazid (INH) was most common (11.1%) followed by streptomycin (SM) (10%), rifampin (RIF) (4.3%), ethambutol (EMB) (2.2%), and pyrazidimide (PZA) (1.1%). A history of previous tuberculosis therapy (odds ratio [OR] = 2.71, 95% confidence interval [CI] = 1.34-5.48) and being born outside the United States and Puerto Rico (OR = 4.76, CI = 1.69-13.39) were independently associated with drug resistance. Because of the high proportion of drug-resistant tuberculosis in Puerto Rico we recommend (1) that all persons in Puerto Rico in whom tuberculosis is diagnosed should initially receive four-drug therapy (INH, RIF, EMB, and PZA), (2) that susceptibility testing be done on initial Mycobacterium tuberculosis isolates from all patients, and (3) that those with a history of previous tuberculosis therapy or those who are foreign-born have very careful clinical and microbiologic follow-up.