Abstract Several experimental studies have reported that the anticarcinogenic properties of dietary soy play an important role in preventing colorectal cancer. However, few epidemiologic studies have examined this association in general populations and their findings have been inconsistent. We investigated the association between dietary soy and isoflavone intake and incidence of colorectal cancer in a prospective cohort study of 83,063 Japanese men and women, ages 45 to 74 years. Dietary soy and isoflavone intake was measured through a validated food frequency questionnaire in 1995 and 1998. Throughout 2004, a total of 886 cases of colorectal cancer were newly identified (291 proximal colon, 286 distal colon, and 277 rectum). The hazard ratios and 95% confidence intervals (95% CIs) were estimated by fitting a Cox proportional hazards model. The intake of isoflavones, miso soup, and soy food was not associated with colorectal cancer in either men or women. By colorectal cancer subsite, the risk of proximal colon cancer in men decreased with increasing consumption of isoflavones, miso soup, and soy food. Compared with men in the lowest quartiles of isoflavones, miso soup, and soy food intake, the hazard ratios in the highest quartiles were 0.55 (95% CI, 0.33-0.92), 0.72 (95% CI, 0.43-1.21), and 0.51 (95% CI, 0.30-0.87), respectively. The results showed no association for distal colon and rectal cancer in men or for subsites of colorectal cancer in women. These findings suggest that the intake of isoflavones, miso soup, and soy food has no substantial effect on the risk of colorectal cancer in Japanese men and women. (Cancer Epidemiol Biomarkers Prev 2008;17(8):2128–35)