Context: Laboratory and epidemiological data suggest that folic acid may have an antineoplastic effect in the large intestine. Objective: To assess the safety and efficacy of folic acid supplementation for preventing colorectal adenomas. Design, Setting, and Participants: A double-blind, placebo-controlled, 2-factor, phase 3, randomized clinical trial conducted at 9 clinical centers between July 6, 1994, and October 1, 2004. Participants included 1021 men and women with a recent history of colorectal adenomas and no previous invasive large intestine carcinoma. Intervention: Participants were randomly assigned in a 1:1 ratio to receive 1 mg/d of folic acid (n=516) or placebo (n=505), and were separately randomized to receive aspirin (81 or 325 mg/d) or placebo. Follow-up consisted of 2 colonoscopic surveillance cycles (the first interval was at 3 years and the second at 3 or 5 years later). Main Outcome Measures: The primary outcome measure was occurrence of at least 1 colorectal adenoma. Secondary outcomes were the occurrence of advanced lesions (≥25% villous features, high-grade dysplasia, size ≥1 cm, or invasive cancer) and adenoma multiplicity (0, 1-2, or ≥3 adenomas). Results: During the first 3 years, 987 participants (96.7%) underwent colonoscopic follow-up, and the incidence of at least 1 colorectal adenoma was 44.1% for folic acid (n=221) and 42.4% for placebo (n=206) (unadjusted risk ratio [RR], 1.04; 95% confidence interval [CI], 0.90-1.20; P=.58). Incidence of at least 1 advanced lesion was 11.4% for folic acid (n=57) and 8.6% for placebo (n=42) (unadjusted RR, 1.32; 95% CI, 0.90-1.92; P=.15). A total of 607 participants (59.5%) underwent a second follow-up, and the incidence of at least 1 colorectal adenoma was 41.9% for folic acid (n=127) and 37.2% for placebo (n=113) (unadjusted RR, 1.13; 95% CI, 0.93-1.37; P=.23); and incidence of at least 1 advanced lesion was 11.6% for folic acid (n=35) and 6.9% for placebo (n=21) (unadjusted RR, 1.67; 95% CI, 1.00-2.80; P=.05). Folic acid was associated with higher risks of having 3 or more adenomas and of noncolorectal cancers. There was no significant effect modification by sex, age, smoking, alcohol use, body mass index, baseline plasma folate, or aspirin allocation. Conclusions: Folic acid at 1 mg/d does not reduce colorectal adenoma risk. Further research is needed to investigate the possibility that folic acid supplementation might increase the risk of colorectal neoplasia. Trial Registration: clinicaltrials.gov Identifier: NCT00272324.