Background and aims Nalmefene has been approved in Europe for the treatment of alcohol dependence and subsequently recommended by the UK National Institute for Health and Care Excellence (NICE). This study examines critically the evidence base underpinning both decisions and the issues arising. Methods Published studies of nalmefene were identified through a systematic search, with documents from the European Medicines Agency, the NICE appraisal and public clinical trial registries also examined to identify methodological issues. Results Efficacy data used to support the licensing of nalmefene suffer from risk of bias due to lack of specification of a priori outcome measures and sensitivity analyses, use of post-hoc sample refinement and the use of inappropriate comparators. Despite this evidence for the efficacy of nalmefene in reducing alcohol consumption in those with alcohol dependence is, at best, modest, and of uncertain significance to individual patients. The relevance of existing trial data to routine primary care practice is doubtful. Conclusions Problems with the registration, design, analysis and reporting of clinical trials of nalmefene did not prevent it being licensed and recommended for treating alcohol dependence. This creates dilemmas for primary care clinicians and commissioning organisations where nalmefene has been heavily promoted, and poses wider questions about the effectiveness of the medicines regulation system and how to develop the alcohol treatment evidence base.