Objective: The purpose of this study was to investigate whether folate intake is associated with risk for incident sporadic colorectal adenoma, and whether the association differs according to methylenetetrahydrofolate reductase (MTHFR) genotypes or is modified by intakes of alcohol or other micronutrients in the folate metabolism pathway. Methods: The authors analyzed data from a colonoscopy-based case–control study (n = 177 cases, 228 controls) conducted in North Carolina between 1995 and 1997. Results: The multivariate-adjusted odds ratio (OR) comparing the highest to lowest tertile of total folate intake was 0.61 (95% confidence interval [CI] 0.35–1.05); for MTHFR C677T polymorphism CT and TT genotypes relative to the CC genotype they were, respectively, 1.09 (CI: 0.71–1.66) and 0.68 (CI: 0.29–1.61); and for heavy drinkers (>3 drinks/week) compared to non-drinkers it was 1.67 (CI: 1.00–2.81). The multivariate-adjusted ORs comparing the highest to lowest tertile of total folate intake according to those with the MTHFR CC, CT, and TT genotypes, were, respectively, 0.65 (CI: 0.30–1.39), 0.57 (CI: 0.23–1.44), and 0.22 (CI: 0.02–3.19). For those in the lowest tertile of folate intake who drank more than three drinks a week compared to those who were in the highest tertile of folate intake and did not drink alcohol the OR was 6.54 (CI: 1.96–21.80). There was no substantial evidence for interactions of folate with intakes of methionine, vitamins B2, B6, or B12. Conclusions: These data are consistent with hypotheses and previous findings that higher folate intake may reduce risk for colorectal neoplasms, perhaps especially among those who consume more alcohol.