An elevated plasma homocysteine level is a risk factor for cardiovascular disease and is often observed in other common disorders, including neural tube defects, pregnancy complications, and Alzheimer's disease. Plasma homocysteine level is affected by vitamin intake and by sequence variation in enzymes of homocysteine metabolism. One such enzyme, methylenetetrahydrofolate reductase (MTHFR), synthesizes 5-methyltetrahydrofolate, utilized in homocysteine remethylation to methionine. A variant of the MTHFR gene at base pair 677 is associated with reduced activity, increased thermolability, and hyperhomocysteinemia. This variant has been reported to increase risk of the aforementioned disorders. However, not all studies examining disease risk with respect to MTHFR genotype have reported a statistically significant relation. The current authors hypothesized that the effect of the variant might be stronger in younger age groups, as is the case with other genetic risk factors. Thus, the authors examined data from three North American studies: a study of mothers of spina bifida children and control mothers (1995-1996; n = 136); the National Heart, Lung, and Blood Institute Family Heart Study (1994-1995; n = 537); and a Mayo Clinic study of patients undergoing coronary angiography (1998-1999; n = 504). In each study, the effect of MTHFR genotype on plasma homocysteine level was statistically significant only in younger age groups. Failure to examine younger patients separately may explain why some studies have found no association between the genotype and cardiovascular disease.