The efficacy of naltrexone in the treatment of alcohol use disorder (AUD) has been associated with a set of variables not directly related with the expression of opioid receptors. All the variables have been found to be highly associated with AUD itself or more severe clinical levels of AUD. Given the high association between alcohol metabolizing enzymes (AME) and the outcome of AUD, the present study aims to investigate the role of AME genotype variants in the treatment of AUD with naltrexone. We carried out a 12-week longitudinal clinical trial based on the treatment of AUD patients with naltrexone (N = 101), stratified by different alcohol metabolization genotypes. Genotyping was performed after the inclusion of the patients in the study, based on the individual presence of single nucleotide polymorphisms (SNPs) in the and , and genes. The outcome of alcohol use has been monitored employing the timeline follow-back during the treatment. The (Ile350Val, rs698) and (Glu504Lys, rs671) polymorphisms were associated with a better response to naltrexone treatment, whereas the (Arg370Cys, rs2066702) allelic variant showed a negative outcome. The present study explores a genomic setting for the treatment of AUD with naltrexone. According to our findings, the association between and variants and better outcomes suggests a successful treatment, whereas the mutated allele might lead to an unsuccessful treatment. Further studies should be performed to investigate the relationship between alcohol metabolizing genotypes, the family history of alcohol use disorders and the effect of naltrexone on the outcomes. Genotyping may be a valuable tool for precision-medicine and individualized approach, especially in the context of alcohol use disorders. The small number of subjects was the main limitation of the present study.