Purpose: The precise mechanisms that naltrexone acts on the brain to improve alcohol dependence treatment outcomes is unknown. Naltrexone is a Mu- opioid antagonist that blocks endogenous opioid reward and is thought to reduce alcohol cue-conditioned craving. A number of clinical trials demonstrate naltrexone interacts pharmacogenetically with gene variants that encode proteins implicated in neurotransmission. The Asn40Asp polymorphism of the opioid receptor gene OPRM1 (also known as NCBI tag: rs1799971) is a promising candidate. It has been associated in some studies with better outcomes in naltrexone treatment. Published sample sizes are modest, typically N < 100, and several studies have failed to replicate these findings, including the meta-analysis presented prior to this talk (Hartwell). The current study examined the potential genetic mechanisms associated with response to naltrexone by prospectively examining modulation of alcohol craving by OPRM1 genetic variants (AG and GG genotype) over the treatment episode. The study also applies a new international standard in alcohol craving measurement, recently published Addiction. Methods: Prospective clinical study. 186 alcohol dependent patients were voluntarily enrolled following informed consent in an abstinence-based, 12-week CBT-based outpatient alcohol dependence treatment program. The Alcohol Craving Experience (ACE) measured “anti-craving” properties of medications at eight time points over treatment. Results: 87 patients with the AA genotype and 34 patients with the AG/GG genotype (Asn40Asp) were prescribed naltrexone. Longitudinal linear mixed models examined the effects of naltrexone and OPRM1 on craving over the course of eight treatment sessions. Alcohol craving reduced over treatment (p < 0.001). Patients with the Asn40Asp (AG /GG genotype) had a significantly greater reduction in craving when taking naltrexone (p = 0.017). When individual differences in the trajectory of craving over treatment were controlled within the analysis this effect became non-significant (p > 0.05). Conclusions: Further research is required to examine potential mechanisms which moderate treatment response to naltrexone.