The association between cigarette smoking and colorectal cancer (CRC) has been controversial. To synthesize the available data, we conducted a comprehensive meta-analysis of all prospective studies. A total of 36 studies were included in our meta-analysis. We examined the association between smoking and CRC, colon cancer and rectal cancer in terms of incidence and mortality. Separate analyses were conducted for smoking status, daily cigarette consumption, duration, pack-years and age of initiation. Relative to nonsmokers, current and former smokers had a significantly increased risk of CRC incidence and mortality, respectively. When CRC data were combined with colon/rectal cancer data, current smokers had a significantly increased risk of CRC incidence. All 4 dose–response variables examined—daily cigarette consumption (RR = 1.38 for an increase of 40 cigarettes/day), duration (RR = 1.20 for an increase of 40 years of duration), pack-years (RR = 1.51 for an increase of 60 pack-years) and age of initiation (RR = 0.96 for a delay of 10 years in smoking initiation)—were significantly associated with CRC incidence (all p-values < 0.0001). The relationship between duration of smoking and rectal cancer incidence was also significant. Among the subset of studies that distinguished cancer by site, a higher risk was seen for rectal cancer than for colon cancer for all analyses. Among prospective studies, a consistent association exists between smoking and CRC. The association is stronger for rectal cancer than for colon cancer in the subset of studies that differentiated cancer by site. © 2008 Wiley-Liss, Inc.