In a previous study, we have shown that a 6-month regimen consisting of 2 months of isoniazid, rifampin, pyrazinamide, and streptomycin administered daily (2IRSZ) followed by 4 months of isoniazid and rifampin administered twice weekly (4I2R2) yielded no relapses after 30 months of follow-up. In order to assess the contribution of streptomycin to this treatment regimen, 213 patients with newly detected smear-positive pulmonary tuberculosis were randomly assigned to the following two 6-month treatment regimens: 2IRZ/4I2R2 and 2IRSZ/4I2R2. One hundred seventy-two of the 213 patients (81%) completed therapy, i.e., 116 of 135 patients (86%) treated with 2IRZ/4I2R2 and 56 of 78 patients (72%) treated with 2IRSZ/4I2R2. Adverse reactions requiring withdrawal of drugs for 7 days or longer were observed in 4.2% of patients (3.7% receiving the 2IRZ/4I2R2 regimen and 5.1% receiving the 2IRSZ/4I2R2 regimen). At the end of treatment, all patients in the 2IRZ/I2R2 series had negative smears and cultures. Two of the 116 patients (1.7%) in the 2IRZ/I2R2 series developed isoniazid resistance in the fourth month of treatment and remained sputum positive at the end of treatment. In the follow-up period, 4 patients (3.4%) treated with 2IRZ/4I2R2 relapsed and 1 (1.8%) treated with 2IRSZ/4I2R2 relapsed. The only significant difference between the 2 regimens was the higher dropout rate among those assigned to the 2IRSZ/4I2R2 regimen.