Aims/hypothesis: To determine whether 6 weeks of daily, moderate alcohol consumption increases expression of the gene encoding adiponectin (ADIPOQ) and plasma levels of the protein, and improves insulin sensitivity in postmenopausal women. Methods: In a randomised, open-label, crossover trial conducted in the Netherlands, 36 apparently healthy postmenopausal women who were habitual alcohol consumers, received 250 ml white wine (∼25 g alcohol/day) or 250 ml of white grape juice (control) daily during dinner for 6 weeks. Randomisation to treatment allocation occurred according to BMI. Insulin sensitivity and ADIPOQ mRNA and plasma adiponectin levels were measured at the end of both periods. Insulin sensitivity was estimated using the homeostasis model assessment of insulin resistance (HOMA-IR). Levels of ADIPOQ mRNA in subcutaneous adipose tissue were determined by RT-PCR. Results: All subjects completed the study. Six weeks of white wine consumption reduced fasting insulin (mean±SEM 40.0±3.4 vs 46.5±3.4 pmol/l; p<0.01) and HOMA-IR (1.42±0.13 vs 1.64±0.13; p=0.02) compared with 6 weeks of grape juice consumption. ADIPOQ mRNA levels (1.09±0.15 vs 0.98±0.15; p=0.04) and plasma levels of total (13.1±0.8 vs 12.0±0.8 μg/ml; p<0.001) and high molecular weight (HMW) adiponectin (9.9±1.2 vs 8.8±1.2 μg/ml; p=0.02) significantly increased after alcohol compared with juice consumption. Changes in ADIPOQ mRNA levels correlated with changes in plasma levels of total adiponectin (ρ=0.46; p<0.01). Both fasting triacylglycerol (8.2%; p=0.04) and LDL-cholesterol levels (7.8%; p<0.0001) decreased, whereas HDL-cholesterol increased (7.0%; p<0.0001) after prolonged moderate alcohol intake. No notable adverse effects were reported. Conclusions/interpretation: Moderate alcohol consumption for 6 weeks improves insulin sensitivity, adiponectin levels and lipid profile in postmenopausal women. Furthermore, these data suggest a transcriptional mechanism leading to the alcohol-induced increase in adiponectin plasma levels. Trial registration: ClinicalTrials.gov ID no.: NCT00285909 Partly funded by the Dutch Foundation for Alcohol Research (SAR).