Heterocyclic amines in tobacco smoke and fried meat are activated or detoxified by N-acetyltransferases (NAT1 and NAT2). We identified 379 cases with colorectal cancer (CRC) and 769 sub-cohort members among a cohort of 57,000 members. There were no statistically significant associations between tobacco smoking, consumption of meat (red, processed and fried) and CRC risk. Preference for brown-dark pan-fried meat increased the CRC risk. NAT1 fast acetylators had a significantly higher risk of CRC than NAT1 slow acetylators, whereas NAT2 acetylator status did not affect the CRC risk. There were no statistically significant interactions between tobacco smoking and either NAT1 or NAT2 acetylator status in relation to CRC risk. However, smoking intensity increased CRC risk among carriers of both NAT1 and NAT2 fast. This indicates that N-acetylator status affects the relationship between smoking and CRC risk.