Dietary folate status appears to influence risk for colorectal cancer possibly by alterations in DNA methylation and nucleotide precursor pools. Polymorphisms (677C-->T and 1298A-->C) in methylenetetrahydrofolate reductase (MTHFR), a key enzyme in folate metabolism, determines enzyme activity. The frequency of polymorphisms in the gene varies extensively in different populations. We sought to determine the association between folate status, folate metabolism, DNA methylation, tobacco, alcohol consumption, and the risk of colorectal adenomas in African Americans. Among 58 patients who underwent a clinically indicated colonoscopy, 23 patients with histology confirmed colorectal polyps and 35 patients without were recruited for a case-control study. Blood samples were collected from fasting patients for determination of serum and red blood cell (RBC) folate, homocysteine, vitamin B(12), and methylation status. Polymerase chain reaction (PCR) restriction fragment length polymorphism (RFLP) technique was performed to identify the MTHFR 677 C-->T polymorphism and specific PCR was used to analyze adenomatous polyposis coli (APC) gene-promoter sequence methylation. Among 23 cases, 49 polyps (adenomatous, n = 41 and hyperplastic, n= 8) were identified. Twenty-eight (57%) of the polyps were on the left side and 21 (42%) were on the right side of the colon. There was no association between the presence of colon polyps and levels of folate (serum, RBC), vitamin B(12), or homocysteine. Forty-eight individuals (84%) were homozygous for 677 CC. Of these individuals, 18 (37.5%) had >/=1 colorectal polyps, whereas 30 (62.5%) had no polyps. Nine individuals were heterozygous for 677 CT, and 4 (44%) of these individuals had colon polyps. Eighty-eight percent of the APC gene-promoter sequences tested using peripheral blood DNA from patients were unmethylated. Among the individuals who showed APC methylation, 66% had polyps; 33% were polyp free using their blood DNA. There was highly significant association between smoking and alcohol consumption with the presence of a colon polyp (P= .0006 and P= .05, respectively). In conclusion, the lack of the 677 TT may be a significant risk factor for colon neoplasm in the African-American population. Smoking and alcohol consumption were found to be risk factors for colon polyps. APC gene-promoter sequence methylation found in peripheral blood may be an indicator of risk for polyp formation and an important screening tool.