Red wine contains polyphenol antioxidants that inhibit colorectal cancer (CRC) development in animal studies. We investigated the effect of red wine intake on risk of CRC in the California Men's Health Study (CMHS). CMHS is a prospective, multiethnic cohort of middle-aged men who were members of the Kaiser Permanente (KP) California Health Plans and completed study questionnaires between 2002-2003. Incident CRC were identified from the health plan cancer registries through the end of 2007 (n = 287). To properly account for potential confounding by previous endoscopy screening, we restricted the primary analyses to CMHS men continuously enrolled in KP between 1998-2002 (n = 43,483 and CRC = 176). We used multivariable Cox regression to adjust for important confounders. We did not find an inverse association between moderate red wine intake and risk of CRC. The hazard ratio for consuming >/=1 drink/day (average = 2 drinks/day) was 1.16, 95% confidence intervals 0.56-2.40. There was no linear dose-response. The lack of clear association for red wine intake was consistently observed when we stratified the analyses by CRC stage at diagnosis and cancer site (colon or rectum). Moderate red wine consumption was not associated with reduced risk of colorectal cancer in this population of middle-aged men.