Aim: To compare the effects in alcohol-dependent patients of three pharmacotherapies, disulfiram (DIS), naltrexone (NTX), and acamprosate (ACA), when used with a brief manual-based cognitive-behavioural intervention. Method: We conducted a randomized, open label, multicentre naturalistic study in two phases; first, a 12-week continuously supervised medication, followed by targeted medication (TM) up to 52 weeks in addition to a 67-week follow-up period; altogether 119 weeks (2.5 years), in 243 voluntary treatment-seeking alcohol-dependent adult outpatients. Subjects were randomized 1:1:1 to receive supervised NTX, ACA or DIS, 50, 1998, or 200 mg, respectively, per day, plus a brief manual-based cognitive-behavioural intervention. The patients were met in the second and sixth weeks, and then after 3, 6, and 12 months. The primary outcome measures were the time (days) to first heavy drinking day (HDD), and time during the first 3 months to the first drinking day after medication started. Secondary variables were abstinent days/week (0 drinks/day), average weekly alcohol intake, Alcohol Use Disorder Identification Test (AUDIT), Severity of Alcohol Dependence Data (SADD), and quality of life (QL) measures. Results: All three study groups showed marked reduction in drinking, from baseline to the end of the study. During the continuous medication phase, treatment with DIS 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 TM 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. There were no differences between the NTX and ACA groups in either phase of the study of drinking outcomes. However, SADD scores improved more in the NTX group than the ACA group. Conclusions: Patients allocated to ACA, NTX and DIS combined with brief manual-based cognitive behavioural intervention significantly reduce their alcohol consumption and report improved QL. Supervised DIS appeared superior, especially during the continuous medication period, to NTX and ACA.