Folic acid, vitamin B6, and vitamin B12 act in concert in the one‐carbon metabolism. Supplementation with B vitamin combination may confer a protection against the development of colorectal neoplasia. We aimed to evaluate the effect of combined folic acid, vitamin B6, and vitamin B12 treatment on colorectal adenoma in women from the Women's Antioxidant and Folic Acid Cardiovascular Study (WAFACS). All participants were randomly assigned to either an active treatment group (daily intake of a combination pill of 2.5 mg of folic acid, 50 mg of vitamin B6, and 1 mg of vitamin B12) or to the placebo group. The present study included 1,470 participants who underwent at least one endoscopy after randomization and were followed from April 1998 through June 30, 2007. Compared with placebo, women receiving the active treatment had similar risk of developing at least one adenoma (multivariate‐adjusted rate ratio [RR], 1.00; 95% confidence interval [CI], 0.83–1.20). Treatment was also not associated with risk of adenoma according to subsite (proximal or distal), size (small or large), stage (early or advanced), and the number of adenomas (1 or ≥2). In conclusion, our results indicate no significant effect of combined folic acid, vitamin B6, and vitamin B12 treatment on colorectal adenoma risk among women.