Laboratory and seroepidemiologic studies have suggested that insulin-like growth factor binding protein-3 (IGFBP-3), the main binding protein for IGF-I, may be protective against colorectal cancer. We investigated the association of two polymorphisms (A-202C and G2133C) in the IGFBP3 gene with plasma IGF hormone levels among 887 randomly selected participants in the Multiethnic Cohort study. We found that these two genetic variants were in strong linkage disequilibrium and were both inversely associated with plasma IGFBP-3. However, the effect on plasma IGFBP-3 levels was stronger for the G2133C variant than the A-202C variant. Thus, we assessed the colorectal cancer risk associated with the G2133C in a case-control study of 817 cases and 1,995 controls nested within the Multiethnic Cohort study. Under the assumption of dominant genetic model, carriers of the 1233C allele were at 32% increased risk of colorectal cancer [95 % confidence interval (95% CI) for the odds ratio (OR), 1.07-1.62] and that this effect seemed stronger for the rectum (OR for the C allele, 1.95; 95% CI, 1.35-2.83) than the colon (OR, 1.16; 95% CI, 0.92-1.45). These data suggest that the exon 1 G2133C missense variant in IGFBP3 may be a susceptibility factor for colorectal cancer.