This randomized clinical trial evaluated the relative efficacy of three buprenorphine dosing schedules. Opioid-dependent adults were randomly assigned to receive buprenorphine seven, 3 or 2 days per week for 24 weeks. Daily maintenance doses were 4, 8, 10, or 12 mg of the sublingual buprenorphine solution. Participants who attended the clinic daily received a maintenance dose of buprenorphine daily. Participants who attended the clinic thrice weekly received double their maintenance dose on Monday and Wednesday, followed by a triple dose on Friday. Participants who attended the clinic twice weekly received quadruple their maintenance dose of buprenorphine on Monday and triple their maintenance dose on Friday. Results demonstrated that all dosing regimens were of comparable efficacy in promoting treatment retention, opioid and cocaine abstinence, and reductions in HIV risk behavior (especially as related to drug use) and severity of life problems. Predictor analyses identified sub-populations of opioid-dependent individuals that may have a more positive treatment outcome under each buprenorphine dosing condition. Less-than-daily dosing schedules may provide the opportunity for treatment programs to serve a greater number of opioid-dependent patients and reduce the risk of medication diversion, which may, in turn, have a positive impact on community support of science-based treatment for opioid-dependence.