A double-blind, placebo-controlled clinical trial examining the joint action of naltrexone (NTX) in combination with relapse prevention (RP) therapy for the treatment of cocaine dependence was conducted. Eighty-five participants who achieved initial abstinence during the intake evaluation and detoxification phase of the study were randomized into 1 of 4 combined NTX (0 vs. 50 mg) by therapy (RP vs. Drug Counseling) experimental conditions for the 12-week outpatient treatment phase of the study. A random effects regression model to test for group differences on percentage of cocaine-positive urines indicated a significant time by medication by therapy interaction, suggesting less cocaine use over time among subjects receiving RP-50 mg than those in the other conditions. No differences were found for retention or time until first cocaine-positive urine. Naltrexone was well tolerated by participants, with acceptable rates of medication compliance observed. Treatment integrity measures confirmed successful manipulation of the psychotherapy. These results are consistent with the notion that substance use in dependent patients can be reduced with a combination of coping skills training and pharmacologic treatments.