Among 324 cases of culture-proven tuberculosis from 1988 to 1996 in a hospital in Milan, Italy, 90 (27,8%) were due to Mycobacterium tuberculosis strains resistant to isoniazid and rifampin. Sixty-one of 69 isolates tested had identical restriction fragment length polymorphism patterns. The prevalent strain tested susceptible only to ethionamide and was also resistant to ethambutol, streptomycin, cycloserine, amikacin, kanamycin, terizodone, ofloxacin, rifabutin, rifapentin, and KRM 1648. The median survival time was 94 days, Multivariate analysis showed a trend toward better outcome in the period 1994–1996 (hazard ratio, 4.16; P < .001), and extrapulmonary localization of tuberculosis was the only other independent predictor of a negative outcome (hazard ratio, 2.1; P = .019). The delay from symptoms to beginning of therapy did not seem to be a determining factor in survival time. Standard antituberculosis therapy with four drugs (isoniazid, rifampin, ethambutol, and pyrazinamide) had a higher efficacy than did other regimens with fewer drugs but without a statistically significant difference.