It has been proposed that hyperinsulinemia is involved in colon carcinogenesis. An association between post-load plasma glucose (PLG) levels and risk of colorectal cancer mortality would be consistent with this hypothesis. We used data from the Chicago Heart Association Detection Project in Industry to examine the associations of nonfasting PLG and other variables related to the insulin resistance syndrome (i.e., systolic blood pressure, body mass index, uric acid, and resting heart rate) with colorectal cancer mortality. After excluding participants reporting a history of diabetes, 191 and 126 colorectal cancer deaths occurred among 20,433 men and 15,149 women, respectively. In multivariate Cox regression analysis, there was a positive relationship between PLG levels and colorectal cancer mortality for women (P for trend = 0.08) but not for men. When men and women were combined, a trend (P = 0.05) for PLG remained. Examination of clustering of insulin resistance syndrome-related risk factors revealed that men with at least 3 of 4 risk factors (i.e., in the highest quartile of the sex-specific distribution for PLG, systolic blood pressure, body mass index, or resting heart rate) had a relative risk (RR) of 1.67 [95% confidence interval (CI), 1.04-2.70] as compared with men who were not in the upper quartile for any of these factors. For women, the RR was 1.29 (95% CI, 0.70-2.37). For men and women combined, the RR was 1.50 (95% CI, 1.03-2.19). These findings provide evidence for a modest association of PLG and insulin resistance syndrome with colorectal cancer mortality and support the insulin hypothesis.