OBJECTIVE: Epidemiological studies suggest that moderate alcohol consumers have enhanced insulin sensitivity and a reduced risk of type 2 diabetes. Adiponectin, an adipocyte-derived plasma protein, has been found to be negatively associated with adiposity and positively associated with insulin sensitivity. Moderate alcohol consumption may increase adiponectin, which in turn causes a decrease of tumor necrosis factor (TNF)-alpha. A decreased TNF-alpha level may consequently increase insulin sensitivity. RESEARCH DESIGN AND METHODS: To test this hypothesis, we performed a randomized crossover partially diet-controlled study. A total of 23 healthy middle-aged male subjects consumed daily four glasses of whisky (40 g ethanol) or tap water with dinner during two successive periods of 17 days. RESULTS: Moderate alcohol consumption increased plasma adiponectin level (11%; P = 0.0002) but did not affect plasma TNF-alpha level. An increase in insulin sensitivity index was observed in an insulin-resistant subgroup (21%; P = 0.11), which positively correlated with the relative alcohol-induced increase in plasma adiponectin level (r = 0.73, P = 0.02). CONCLUSIONS: The experimental results are in agreement with observational data. Moderate alcohol consumption improved insulin sensitivity in relatively insulin-resistant middle-aged men, an effect that may be mediated through alcohol-induced increases in adiponectin.