Disulfiram (Antabuse) is being used in outpatient clinical trials to determine its efficacy as a treatment for cocaine dependence. This inpatient randomized, double-blind, placebo-controlled, within-subjects study was conducted to determine whether disulfiram (placebo, 250 or 500 mg/day) alters responses to acute intranasal cocaine (placebo, 1 or 2 mg/kg) administration. Effects of disulfiram on cocaine pharmacokinetics, physiological, and behavioral responses were determined. Disulfiram treatment increased plasma cocaine concentrations three to six times and significantly increased cocaine-associated cardiovascular responses, but did not significantly alter behavioral responses to cocaine. These interactions should be considered in the decision regarding disulfiram treatment in cocaine dependent patients.