In 1996, the US Food and Drug Administration mandated the fortification of grain products with folic acid, a nutrient that has been associated with lower risk of colorectal neoplasia. We assessed the relation of plasma folate and homocysteine and colorectal adenoma recurrence separately in 2 studies: the first involved an intervention of a cereal supplement that contained folic acid, wheat bran fiber (WBF), and the second was conducted primarily during postfortification of the food supply using ursodeoxycholic acid (UDCA). Analyses were stratified for multivitamin use. Results show that plasma folate and homocysteine concentrations were associated with adenoma recurrence among nonusers of multivitamins only. Among nonmultivitamin users, the odds ratio [OR] (95% confidence interval [CI]) for those in the highest versus the lowest folate quartile was 0.65 (0.40-1.06) for the WBF study and 0.56 (0.31-1.02) for the UDCA; likewise, individuals in the highest versus the lowest quartile of homocysteine had higher odds of adenoma recurrence, in both the WBF (OR = 2.25; 95% CI = 1.38-3.66) and UDCA (OR = 1.93; 95% CI = 1.07-3.49) populations. Analyses comparing multivitamin users to different plasma folate concentrations among nonusers show that odds of recurrence for supplement users was lower only when compared to nonusers who had lower concentrations. Our results show that higher plasma folate or lower homocysteine levels are associated with lower odds of recurrence among nonusers of multivitamins in both studies. Our finding, suggesting that multivitamins or supplemental folate only benefit individuals with lower plasma folate concentrations, should be taken into consideration when designing and interpreting results of intervention studies.