© 2016 The British Pharmacological Society Background and Purpose: The opioid antagonist nalmefene (selincro®) was approved for alcohol-related disorders by the European Medicines Agency in 2013. However, there have been no studies regarding the effectiveness of nalmefene when alcohol is used in combination with cocaine. Experimental Approach: Using operant alcohol self-administration in Wistar rats and qRT-PCR, we evaluated (i) the dose–response curve for s.c. and p.o. nalmefene; (ii) the effects of nalmefene with increasing concentrations of alcohol; (iii) the efficacy of nalmefene on cocaine-potentiated alcohol responding; and (iv) the gene expression profiles of histone deacetylases (Hdac1–11) in peripheral blood in vivo and in the prefrontal cortex, heart, liver and kidney post mortem. Key Results: S.c. (0.01, 0.05, 0.1 mg·kg−1) and p.o. (10, 20, 40 mg·kg−1) nalmefene dose-dependently reduced alcohol-reinforced responding by up to 50.3%. This effect of nalmefene was not dependent on alcohol concentration (10, 15, 20%). Cocaine potentiated alcohol responding by approximately 40% and nalmefene (0.05 mg·kg−1) reversed this effect of cocaine. Alcohol increased Hdac gene expression in blood and nalmefene prevented the increases in Hdacs 3, 8, 5, 7, 9, 6 and 10. In the other tissues, alcohol and nalmefene either did not alter the gene expression of Hdacs, as in the prefrontal cortex, or a tissue-Hdac-specific effect was observed. Conclusions and Implications: Nalmefene might be effective as a treatment for alcohol-dependent patients who also use cocaine. Also, the expression of Hdacs in peripheral blood might be useful as a biomarker of alcohol use and drug response.