A controlled clinical trial of the three Short Course Chemotherapy (SCC) regimens was carried out at the Lady Willingdon State Tuberculosis Centre, Bangalore and Tuberculosis Research Centre, Madras with the collaboration of National Tuberculosis Institute, Bangalore. The regimens were (1) R3: (rifampicin, streptomycin, isoniazid and pyrazinamide daily for 3 months (3RSHZ); (2) R5: same as regimen R3, followed by streptomycin, isoniazid, pyrazinamide twice weekly for 2 months (3RSHZ/2S2H2Z2); (3) Z5: same as regimen R5 but without rifampicin (3SHZ/2S2H2Z2). Newly diagnosed tuberculosis patients who were aged 12 years or more had no history of previous treatment and two sputum cultures positive for M.tuberculosis were taken to the study and allocated at random to one of the above stated three regimens. The patients were given supervised chemotherapy as out patients. Sputum specimens were examined by fluorescent microscopy, culture by modified Petroff's method, tested for sensitivity to INH, rifampicin, streptomycin and ethambutol. The follow up was done by sputum smear and culture examination at the end of every month for 2 years. The distribution of various pre treatment characteristics like age, sex, and initial sensitivity status were similar in the three series. At the end of 3 months, of the 455 patients on R3, and R5 series, 96% with drug sensitive organism became culture negative and of 235 on Z5 series 93% became culture negative. For R5 and Z5 series favourable response at the end of chemotherapy were 96%, 99% and 97% respectively. In all, 6 patients (3 R3 & 3 Z5) were classified as having unfavourable response. At the end of 24th month from the date of start of treatment, 20% of the 200 patients on R3, 4% of 187 patients on R5 and 13% of 199 patients on Z5 had bacteriological relapse. The difference between R3 and Z5 series was highly significant. (p = 0.00001). The relapse rates in R3 & Z5 series were significantly higher than that in R5. Of the 57 patients with initial drug resistance organisms in R3 and R5 series combined 4 had an unfavourable response to treatment compared with 13 of 26 in the Z5 series (p = 0.0001). Of the 4 patients with an unfavourable response in R3 and R5 series combined, resistance to rifampicin emerged in 2 patients. Complaints of arthralgia were made by 45% of the R3 and R5 patients combined and 70% of Z5 patients (p = 0.00001). However, chemotherapy was modified in only 5 and 12% respectively. Jaundice occurred in 7% of the R3 and R5 patients and 1% of the Z5 patients (p = 0.0001).