Purpose: Previous data has demonstrated a nonlinear relationship between alcohol consumption and cardiovascular disease (CVD) risk. An understudied area of research is how moderate ethanol interacts with other components of diet to influence underlying risk for CVD. Increased intake of omega-6 (n-6) polyunsaturated fatty acids and deficits in omega-3 (n-3) PUFA have been linked to heightened prevalence of CVD and other diseases that overlap with those impacted by moderate alcohol consumption. The purpose of the present study was to examine the effects of moderate ethanol consumption and PUFA composition on risk for CVD and liver functioning in mice. Subjects: Adult C57BL/6J mice (n=12/sex) were exposed for 15 weeks to ethanol or maltose dextrin (control) in the drinking water and concurrently fed a diet comprised of a high or balanced n-6:n-3 ratio diet. Methodology: Ethanol-exposed mice were maintained on an 18% ethanol solution for 12 weeks, controls received isocalorically matched maltose dextrin in their drinking water. Fluid intake and body weight were measured every 48 hr and food intake once per week. Blood was collected to assess lipid profiles, glucose, and liver function enzyme activity. Fluid intake, food intake, and body weight were analyzed to assess overall consumption across time. It was hypothesized that moderate ethanol consumption combined with a balanced compared to a high n-6:n-3 diet would yield differential synergistic protective or adverse effects, respectively, on markers of metabolic and liver function indicative of reduced or elevated risk for chronic disease. Results: Independent of diet, ethanol-consuming mice displayed significantly higher levels of HDL cholesterol and lower levels of AST, ALT and AP liver enzyme activity. There were trends for lower triglyceride levels in ethanol-exposed mice, and lower levels of LDL in mice consuming the n-3 diet, with the lowest levels of triglycerides and LDL in ethanol-treated mice maintained on the n-3 diet. Conclusion: These findings indicate favorable effects of moderate ethanol consumption on liver function and lipid profile markers associated with CVD, with potential further benefits in combination with an n-3 diet. These results add to a growing literature examining protective effects of moderate alcohol consumption on CVD risk.