Fifteen subjects dependent on both opioids and cocaine completed an ascending and tapering schedule of buprenorphine dosing, with maintenance for 21 days at each dose of buprenorphine (4, 8, 12, 16 mg sublingual daily) during both ascending and tapering phases. Higher doses of buprenorphine led to greater reductions in opioid use: 64.7% of subjects were opioid abstinent for 3 weeks at the 16-mg dose compared to 27.3% at the 4-mg ascending dose. The proportion of cocaine-positive urine toxicologies was significantly lower during buprenorphine tapering (12 mg, 8 mg, 4 mg) compared to ascending doses up to 8 mg, with intermediate results at 12 mg and 16 mg during the ascending phase (F value = 6.6, df = 8,813, p < 0.001). Self-reported days, times, and quantity of cocaine used per week showed a similar pattern of intermediate reductions at the 12-mg and 16-mg dose during the ascending phase and significantly reduced values during the descending schedule. There were no significant buprenorphine dose effects on cocaine euphoria. This study indicates that buprenorphine dose has a significant and substantial impact on opioid use and a significant but less robust impact on cocaine use, with higher doses and longer time on buprenorphine leading to attenuated cocaine use.