Presented here are the cases of three siblings with multidrug-resistant tuberculosis who demonstrated increased antituberculous-drug resistance during the periods in which they received standard regimens of directly observed, short-course chemotherapy that were administered before the susceptibility patterns of their Mycobacterium tuberculosis isolates had been checked. More specifically, they acquired resistance to drugs they received as part of ineffective standard treatment and retreatment regimens. Development of antituberculous-drug resistance through inadvertent, inadequate therapy appears to be the most likely explanation for the increased resistance seen in these three patients.