OBJECTIVES To assess, from the perspective of national health insurance, the cost-effectiveness of psychosocial support plus nalmefene versus psychosocial support alone, for the treatment of adult patients with alcohol dependence who have a high drinking risk level, without physical withdrawal symptoms, and who do not require immediate detoxification. METHODS A cost-effectiveness Markov model, originally developed for the Single Technology Appraisal by the National Institute for Health and Care Excellence of Nalmefene, was adapted to the Greek healthcare setting to evaluate the health effects and associated costs of compared therapeutic options. The model consisted of a short-term phase (1 year: based on clinical trials assessing nalmefene) and a long-term phase (2-5 years) evaluating patient progression and a second-line abstinence treatment option. Clinical inputs were derived from ESENSE1 (NCT00811720), ESENSE2 (NCT00812461) and SENSE (NCT00811941) clinical trials and epidemiological data from the national statistical authority and published literature. All direct costs with respect to treatment of alcohol dependence and the management of alcohol-attributable harmful events were considered reflecting the year 2014.  RESULTS Over a 5-year horizon, the addition of nalmefene to psychosocial support led to the avoidance of 3,071 alcohol-attributable diseases/injuries and 851 deaths per 100,000 patients. Nalmefene plus psychosocial support reduced the proportion of high-risk and very high-risk drinkers (23% versus 37% with psychosocial support alone) and increased the number of controlled drinkers (61% versus 45%). In the base-case, the nalmefene plus psychosocial support arm cumulated a 5-year incremental cost of €160 and an incremental QALY of 0.024. The incremental cost-effectiveness ratio of €1,928 was considerably low with respect to the decision threshold of €16,000 per QALY gained (equal to the GDP per capita of Greece).  CONCLUSIONS Treatment with nalmefene is cost-effective in the Greek healthcare setting leading to significant reductions of alcohol dependent patients and alcohol-attributable harmful events.