Diet is a strong moderator of systemic inflammation, an established risk factor for colorectal cancer (CRC). The dietary inflammatory index (DII) measures the inflammatory potential of individuals' diets. The association between the DII and incident CRC was examined, using the National Institutes of Health–American Associations of Retired Persons Diet and Health Study individuals (n 489 422) aged 50–74 years at recruitment, starting between 1995–6, and followed for a mean of 9·1 (sd 2·9) years. Baseline data from a FFQ were used to calculate the DII; higher scores are more pro-inflammatory, and lower scores are more anti-inflammatory. First, primary CRC diagnoses were identified through linkage to state cancer registries. Anatomic location and disease severity also were examined. Cox proportional hazards models estimated CRC hazard ratios (HR) and 95 % CI using quartile 1 as the referent. DII quartile 4 compared to quartile 1 was associated with CRC risk among all subjects (HR 1·40, 95 % CI 1·28, 1·53; P for trend < 0·01). Statistically significant associations also were observed for each anatomic site examined, for moderate and poorly differentiated tumours, and at each cancer stage among all subjects. Effects were similar when stratified by sex; however, results were statistically significant only in males. The only result reaching statistical significance in females was risk of moderately differentiated CRC tumours (DII quartile 4 v. quartile 1 HR 1·26, 95 % CI 1·03, 1·56). Overall, the DII was associated with CRC risk among all subjects. The DII may serve as a novel way to evaluate dietary risk for chronic disorders associated with inflammation, such as CRC.