Approximately 5% to 15% of all colorectal cancers (CRC) have an activating BRAF somatic mutation, which may be associated with a distinct risk profile compared with tumors without BRAF mutations. Here, we measured the prevalence and epidemiologic correlates of the BRAF V600E somatic mutation in cases collected as a part of a population-based case-control study of CRC in northern Israel. The prevalence of BRAF V600E was 5.0% in this population, and the mutation was more likely to be found in tumors from cases who were of Ashkenazi Jewish descent [odds ratio (OR), 1.87; 95% confidence interval (95% CI), 1.01-3.47], female (OR, 1.97; P = 1.17-3.31), and older (73.8 years versus 70.3 years; P < 0.001). These results were similar when restricting to only tumors with microsatellite instability. Whether smoking was associated with a BRAF somatic mutation depended on gender. Although men were less likely to have a tumor with a BRAF somatic mutation, men who smoked were much more likely to have a tumor with a somatic BRAF mutation (OR(interaction), 4.95; 95% CI, 1.18-20.83) than women who never smoked. We note the strong heterogeneity in the reported prevalence of the BRAF V600E mutation in studies of different ethnicities, with a lower prevalence in Israel than other Western populations but a higher prevalence among Jewish than non-Jewish Israeli cases. Epidemiologic studies of CRC should incorporate somatic characteristics to fully appreciate risk factors for this disease.