Technical Abstract: Increased circulating insulin-like growth factor-I (IGF-I) concentrations, frequently adjusted for IGF binding protein-3 (IGFBP-3), have been associated with increased risk of several types of cancer, including colon, prostate and breast. Studies have suggested that alcohol may affect IGF-I and/or IGFBP-3; however, controlled feeding studies to assess alcohol's effects on IGF-I or IGFBP-3 serum concentrations have not been conducted. We therefore investigated whether chronic, moderate alcohol intake affected IGF-I and/or IGFBP-3 in a controlled, crossover feeding study. Fifty-three postmenopausal women were randomly assigned to consume 0 g (control), 15 g (one drink), or 30 g (two drinks) of alcohol daily for eight weeks, and rotated through the other two intake levels in random order. All foods and beverages were provided during the intervention. Individuals were monitored and calories adjusted to maintain constant weight, and serum was collected at the end of each diet period. As compared to 0 g/day of alcohol, IGF-I concentrations were unchanged by 15 g/day [0.0%, 95% confidence interval (CI) = -3.2 to 3.5%] but significantly changed by -4.9% (95% CI = -8.0 to -1.6%) with 30 g/day, while IGFBP-3 concentrations significantly increased 3.0% (95% CI = 0.4 to 5.6%) with 15 g/day, but only marginally increased by 1.8% (95% CI = -0.9 to 4.5%) with 30 g/day of alcohol. This is the first controlled diet study to find that, in postmenopausal women, alcohol consumption reduces the amount of serum IGF-I potentially available for receptor binding when weight is kept constant. These findings suggest that the impact of alcohol intake should be considered in studies of IGF-I, IGFBP-3 and cancer in postmenopausal women.