Acamprosate, naltrexone and disulfiram have been shown to reduce drinking and/or improve abstinence. We performed a randomized, multicenter study in two phases; first, 12-week continuous supervised medication, followed by targeted medication up to 52 weeks in addition to a 67-week follow up period. 243 voluntary treatment-seeking alcohol-dependent adult outpatients were randomized 1:1:1 to receive supervised naltrexone, acamprosate or disulfiram, 50 mg, 1998 mg or 200 mg respectively per day and brief manual-based cognitive behavioral intervention. The primary outcome measures were the time to first heavy drinking day (HDD) and time during the first 3 months to the first drinking day after medication started. All three study groups showed marked reduction in drinking from baseline to the end of the study. During the continuous medication phase, treatment with disulfiram was more effective in reducing HDDs and average weekly alcohol consumption, and increasing time to the first drink as well as the number of abstinent days. During the targeted medication period, there were no significant differences between the groups in time to first HDD and days to first drinking, but the abstinence days were significantly more frequent in the DIS group than ACA and NTX. However, naltrexone was better than acamprosate in reducing the severity of alcohol dependence indicator SADD scores. We conclude that acamprosate, naltrexone and disulfiram combined with brief manual-based cognitive behavioral intervention significantly reduce alcohol consumption and improve the quality of life. Supervised disulfiram was superior, especially during the continuous medication period, to naltrexone and acamprosate.