Background: A large proportion of colorectal cancers (CRC) are thought to be associated with unhealthy dietary and lifestyle exposures, particularly energy excess, obesity, hyperinsulinemia and hyperglycemia. It has been suggested that these processes stimulate the production of toxic reactive carbonyls from sugars such as glyceraldehyde. Glyceraldehyde contributes to the production of a group of compounds known as glyceraldehyde-derived advanced glycation end-products (glycer-AGEs) which may promote CRC through their pro-inflammatory and pro-oxidative properties. The objective of this study nested within a prospective cohort was to explore the association of circulating glycer-AGEs with risk of CRC. Methods: 1,055 CRC cases (colon n = 659; rectal n = 396) were matchced (1:1) to control subjects. Circulating glycer-AGEs were measured by a competitive enzyme-linked immunosorbent assay. Multivariable conditional logistic regression models were used to calculate odds ratios (OR) and 95% confidence intervals (95% CI), adjusting for potential confounding factors including smoking, alcohol, physical activity, body mass index, and diabetes status. Results: Elevated glycer-AGEs levels were not associated with CRC risk (highest vs. lowest quartile, 1.10; 95% CI, 0.82-1.49). Sub-group analyses showed possible divergence by anatomical sub-sites (OR for colon cancer = 0.83; 95% CI, 0.57-1.22; OR for rectal cancer = 1.90; 95% CI, 1.14-3.19; pheterogeneity = 0.14). Conclusions: In this prospective study, circulating glycer-AGEs were not associated with risk of colon cancer, but showed a positive association with the risk of rectal cancer. Impact: Further research is needed to clarify the role of toxic products of carbohydrate metabolism and energy excess in CRC development.