To investigate the anti-tuberculosis drug resistance pattern of pulmonary tuberculosis isolates in southern Taiwan, we performed a hospital-based surveillance at a southern Taiwan medical centre from 1996 to 2000. The combined drug resistance rates to at least one of four first-line agents (isoniazid, rifampicin, ethambutol, streptomycin) was 52.4%, and to both isoniazid and rifampicin was 11.4%, indicating high resistance rates compared with those reported in the World Health Organization (WHO)/International Union Against Tuberculosis and Lung Disease (IUATLD) global project and in northern Taiwan. The resistance rates to two second-line drugs, cycloserine, and kanamycin, were 75.7 and 23.7%, respectively. A significant decreasing trend in resistance rates to all tested drugs except streptomycin was observed during the 5-year period. The resistance rates in 1996 and 2000 were 43.1 and 16.4% for isoniazid, 23.4 and 9.5% for rifampicin, 23.4 and 12.1% for ethambutol, 92.7 and 50.9% for pyrazinamide. The combined drug resistance rate may not be the most accurate tool as it includes previously treated cases that may inflate the resistance rate and cases without a history of treatment. However, the observation of trends in the susceptibility of pulmonary tuberculosis with the increasing percentages of tuberculosis patients receiving the complete treatment course and the decreasing percentages of cases lost to follow-up in Kaohsiung after the institution of new governmental regulations for case management in 1997, suggest that such intervention programs are useful.