Thirteen opioid-dependent outpatients participated in a double-blind, placebo-controlled, crossover trial. Twenty-one days of daily sublingual buprenorphine administration were compared to 21-days of alternate-day buprenorphine administration where patients received twice their daily maintenance dose every other day with placebo on the interposed day. Observer- and subject-rated measures of opioid agonist and withdrawal effects, pupillary diameter, and dose identifications were collected daily. Ten subjects (77%) completed the study (n = 6, 4 mg/70 kg; n = 4, 8 mg/70 kg); 8 subjects (62%) participated in a second crossover. Sixteen of seventeen measures of opioid agonist and withdrawal effects obtained during alternate-day administration did not differ significantly from those obtained during daily dosing in the ten subjects completing the study. The only significant difference observed was in subject-rated agonist effects, which were significantly lower during alternate-day than daily administration. No differences were observed between treatments on any measure for the eight subjects completing a second crossover. These data suggest that buprenorphine can be administered safely every 48 hours by doubling the maintenance dose. This alternate-day schedule permits patients to attend the clinic less frequently without the risk of diversion associated with take-home doses, may be cost-effective for programs, and may be useful in settings in which travel to the clinic is a barrier to treatment.