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This study aimed to replicate and extend prior research showing that the targeted use of naltrexone is a useful strategy to reduce heavy drinking. We compared the effects of naltrexone with those of placebo in a sample of 163 individuals (58.3% male) whose goal was to reduce their drinking to safe limits. Patients received study medication (ie, naltrexone 50 mg or placebo) and were instructed to use it daily or targeted to situations identified by them as being high risk for heavy drinking. An interactive voice response system was used to obtain daily reports of drinking and medication use during the 12-week trial. Analyses were conducted using hierarchical linear modeling, with sex as a potential moderator variable. On the primary outcome measure, mean drinks per day, at week 12, men in the targeted naltrexone group drank significantly less than patients in the other groups did. On a secondary outcome measure, drinks per drinking day, during week 12, the targeted naltrexone group drank significantly less than the other groups did, with no moderating effect of sex. These results support the use of a targeted approach to reduce drinking among heavy drinkers, particularly men, but argue for the use of additional strategies or more efficacious medications than naltrexone to increase the effects of such an intervention.