OBJECTIVE This article describes the process by whichthe COMBINE investigators evaluated and chose the two pharmacotherapies to be studied in COMBINE. METHOD The pharmacotherapies were chosen through a consensus process that involved the evaluation of neuropharmacological agents known to modify alcohol consumption or other alcohol-related behaviors in animals and humans. Medications were classified according to the published evidence, with the highest ranking given to those with evidence of efficacy in human clinical trials. The investigators also considered evidence for safety, potential drug-drug interactions, management of side effects, optimal dose, treatment duration, availability of the medication and integration with the psychosocial therapies. The full evaluation required conducting two pilot studies and the development of an instrument to monitor safety, the COMBINE Systematic Assessment for Treatment Emergent Events. RESULTS Naltrexone, at a dose of 100 mg per day, and acamprosate, at a dose of 3,000 mg per day, were chosen for the study. The medications were administered for a period of 4 months, concurrent with the COMBINE psychosocial therapies CONCLUSIONS The results of the decision making with respect to medications and safety monitoring resulted in a well-planned and well-executed study that minimized risks to the participants.