Background: Cigarette smoking has been associated with microsatellite instability in sporadic colon cancer. Most microsatellite-unstable colon cancers have widespread methylation of CpG islands (i.e., the CpG island methylator phenotype [CIMP]), and many of these tumors harbor the V600E BRAF mutation. We investigated whether the association between smoking and all colon cancers could be explained through induction of CIMP and/or BRAF mutations. Methods: We evaluated 1315 case patients with colon cancer and 2392 control subjects in a population-based study. Demographic information, including smoking history, was obtained in an interview. Microsatellite instability was determined primarily by evaluation of the mononucleotide repeat BAT-26. CIMP was determined by sodium bisulfite modification of DNA followed by methylation-specific polymerase chain reaction amplification of CpG islands in hMLH1, p16, and MINTS1, -2, and -31. Tumors were scored as CIMP high (i.e., ≥2 CpG islands methylated) or CIMP low (i.e., <2 CpG islands methylated). BRAF V600E mutations were identified by sequencing. Logistic regression was used to quantify relationships among smoking, CIMP, and BRAF. All statistical tests were two-sided. Results: Heavy smoking (i.e., >20 cigarettes per day), compared with nonsmoking, was associated with an increased risk of CIMP-high colon cancer (odds ratio [OR] = 2.06, 95% confidence interval [CI] = 1.43 to 2.97) and also with BRAF V600E mutations (OR = 3.16, 95% CI = 1.80 to 5.54). The association between cigarette smoking and the risk of colon cancer was limited to the minority of tumors that were CIMP high and BRAF wild type or CIMP high and BRAF mutated (for heavy smokers, OR = 1.91, 95% CI = 1.23 to 2.97, and OR = 2.85, 95% CI = 1.53 to 5.29, respectively). All relationships above showed a statistically significant relationship to amount smoked (P trend <.001 for all, except that relationship with tumors that were CIMP high and BRAF wild type, for which P trend = .008) and were independent of microsatellite instability. Conclusions: Previously identified associations between smoking and colon cancer, whether microsatellite unstable or stable, appear to be explained by the association of smoking with CIMP and BRAF mutations.