Tuberculosis patients may have Mycobacterium tuberculosis in their sputum at the end of treatment, and may show new drug resistance, due to either inadequate treatment of the original episode or reinfection with a new strain during therapy. In a cohort study of mineworkers with tuberculosis in South Africa, 57 of 438 patients had positive sputum cultures 6 months after recruitment in 1995. Of the 31 patients who initially had fully sensitive strains, 3 developed multidrug resistance (MDR) and 3 single-drug resistance (SDR). Of the 6 who started with SDR, 3 became MDR. HIV infection was not associated with drug resistance at enrollment or 6 months later. We compared pairs of DNA fingerprints from isolates of M. tuberculosis at recruitment and 6 months later in the 48 patients for whom we had both available. In 45, the pairs were identical. In 1 patient, although both isolates were fully sensitive, the later fingerprint had 1 less band (transposition). In 2 pairs, the fingerprint patterns were completely different: one seemed to be the result of laboratory error and the other was a true reinfection with an MDR strain. Despite a high risk of infection, with a moderate proportion of background drug-resistant strains (11% SDR, 6% MDR), reinfection is not a common cause of treatment failure or drug resistance at 6 months.