Currently there is no approved pharmacotherapy for amphetamine dependence. Recent human laboratory studies have demonstrated that naltrexone modulates some of the reinforcing effects of amphetamine. The aim of this study was to investigate the efficacy of naltrexone in comparison with placebo in reducing relapse to amphetamine use in amphetamine-dependent patients. Eighty patients who met DSM-IV criteria for amphetamine dependence were randomized to 12 weeks of double-blind naltrexone (50 mg) or placebo treatment. Patients visited the clinic twice weekly to receive medication and relapse prevention therapy and leave urine samples, which were analyzed for drug toxicology and for assessing adherence to medication via detection of naltrexone’s metabolite (6-β-naltrexol). The main outcome measure was abstinence from amphetamine use, as indicated by the total number of negative amphetamine urine samples during 12 weeks of treatment. All missing urine samples were defined for the analysis as positive for amphetamine. Overall, 55 patients (68.8%) completed the trial. The intention-to-treat analysis showed that the naltrexone group had a significantly higher number of amphetamine-negative urine samples compared with the placebo group. Survival analyses showed that the treatment groups differed in rate of continuous abstinence, in both the intention-to-treat and completer samples, in favor of naltrexone treatment. There was a significant reduction in craving levels and self-reported consumption of amphetamine in the naltrexone group compared with the placebo group. Treatment with naltrexone was well tolerated in this sample. This trial demonstrated the efficacy of naltrexone in reducing amphetamine use in amphetamine-dependent individuals.