Background: OSU6162, a monoamine stabilizer, has demonstrated efficacy in reducing alcohol and anxiety-related behaviors in preclinical settings. In a previous randomized, double-blind, placebo-controlled trial involving patients with alcohol dependence (AD), OSU6162 significantly reduced craving for alcohol but did not alter drinking behaviors. This retrospective secondary analysis explores whether genetic predispositions related to AD and associated traits might influence the response to OSU6162 treatment in original trial participants. Methods: Polygenic risk scores (PRSs) were calculated for 48 AD patients using PRSice-2 and genome-wide association study (GWAS) data for (i) alcohol use disorder and alcohol consumption, (ii) problematic alcohol use, (iii) drinks per week, (iv) major depression, and (v) anxiety (case-control comparisons and quantitative anxiety factor scores). Linear regression analyses, adjusted for population stratification, assessed interaction effects between PRSs and treatment type (OSU6162 or placebo) on various clinical outcomes. Results: Significant interactions were found between treatment type and anxiety factor score PRS at the genome-wide significance threshold. In the OSU6162-treated group, a higher anxiety PRS was associated with reductions in the number of drinks consumed (FDR = 0.0017), percentage of heavy drinking days (FDR = 0.0060), and percentage of drinking days (FDR = 0.0017), with a trend toward reduced blood phosphatidylethanol (PEth) levels (FDR = 0.068). These associations were absent in the placebo group. Conclusions: These preliminary findings suggest that anxiety PRS may help predict response to OSU6162 treatment in AD. Further research with larger cohorts and more comprehensive genetic data is needed to confirm these results and advance personalized medicine approaches for alcohol use disorder.