Smoking is a recently established risk factor for colon cancer. We wanted to explore the hypothesis that women may be more susceptible to smoking-attributed colon cancer than men as one of the possible explanations for the high colon cancer risk of Norwegian women. We followed 602,242 participants aged 19 to 67 years at enrollment in 1972-2003, by linkage to national registries through December 2007. We used Cox proportional hazard models to estimate HRs and 95% confidence intervals (CI). During a mean follow-up of 14 years, altogether 3,998 (46% women) subjects developed colon cancer. Female ever-smokers had a 19% (HR = 1.19, 95% CI = 1.09-1.32) and male ever-smokers an 8% (HR = 1.08, CI = 0.97-1.19) increased risk of colon cancer compared with never smokers. For all the four dose-response variables examined, female ever-smokers in the most exposed category of smoking initiation, (HR = 1.48, 95% CI = 1.21-1.81), of daily cigarette consumption (HR = 1.28, 95% CI = 1.06-1.55), of smoking duration (HR = 1.47, 95% CI = 1.11-1.95), and of pack-years of smoking (HR = 1.33, 95% CI = 1.11-1.57) had a significantly increased risk of more than 20% for colon cancer overall and of more than 40% for proximal colon cancer, compared with never smokers. A test for heterogeneity by gender was statistically significant only for ever smoking and risk of proximal colon cancer (Wald χ(2), P = 0.02). Female smokers may be more susceptible to colon cancer and especially to proximal colon cancer than male smokers. Women who smoke are more vulnerable to colon cancer than men.