Proanthocyanidins are a group of polymers of flavanols. Animal and in vitro studies suggest they decrease cancer risk, particularly of colorectal cancer. We used data from an Italian case–control study to investigate whether proanthocyanidins are related to colorectal cancer risk. Cases were 1,953 patients with incident, histologically confirmed colorectal cancer (1,225 colon cancers, 728 rectal cancers). Controls were 4,154 patients admitted for acute, non-neoplastic conditions. A reproducible and valid food frequency questionnaire was used. We estimated odds ratios (ORs) through multiple logistic regression models, including terms for potential confounding factors, and energy intake. A trend of decreasing risk with increasing intake of proanthocyanidins emerged for all classes except monomers. The OR for the highest vs. the lowest quintile of intake was 0.82 for monomers and dimers combined, 0.88 for monomers, 0.75 for dimers, 0.74 for all polymers with three or more mers, 0.84 for trimers, 0.80 for 4–6 mers, 0.79 for 7–10 mers, 0.69 for more than 10 mers, and 0.74 for total proanthocyanidins. The associations were apparently stronger for rectal than for colon cancer, in the absence of significant heterogeneity. These results may explain the protective effect of vegetables and fruit on colorectal cancer.