Aims/hypothesis: The aim of this study was to investigate whether moderate alcohol consumption increases plasma high molecular weight (HMW) adiponectin and/or muscle oxidative capacity. Materials and methods: Eleven lean (BMI 18-25 kg/m2) and eight overweight (BMI ≥27 kg/m2) men consumed 100 ml whisky (∼32 g alcohol) or water daily for 4 weeks in a randomised, controlled, crossover trial. After each treatment period, muscle biopsies and fasting blood samples were collected. Results: Adiponectin concentrations increased (p<0.001) by 12.5% after 4 weeks of moderate alcohol consumption. Moderate alcohol consumption tended to increase HMW adiponectin by 57% (p=0.07) and medium molecular weight adiponectin by 12.5% (p=0.07), but not low molecular weight (LMW) adiponectin. Skeletal muscle citrate synthase, cytochrome c oxidase and β-3-hydroxyacyl coenzyme A dehydrogenase (β-HAD) activity were not changed after moderate alcohol consumption, but an interaction between alcohol consumption and BMI was observed for cytochrome c oxidase (p=0.072) and citrate synthase (p=0.102) activity. Among lean men, moderate alcohol consumption tended to increase cytochrome c oxidase (p=0.08) and citrate synthase activity (p=0.12) by 23 and 26%, respectively, but not among overweight men. In particular, plasma HMW adiponectin correlated positively with activities of skeletal muscle citrate synthase (r=0.64, p=0.009), cytochrome c oxidase (p=0.59, p=0.009) and β-HAD (r=0.46, p=0.056), while such correlation was not present for LMW adiponectin. Whole-body insulin sensitivity and intramyocellular triacylglycerol content were not affected by moderate alcohol consumption. Conclusions/interpretation: Moderate alcohol consumption increases adiponectin concentrations, and in particular HMW adiponectin. Concentrations of HMW adiponectin in particular were positively associated with skeletal muscle oxidative capacity.