Background/Objectives: Unlike most Western populations, MTHFR 677T is a rare allele and a risk factor for a variety of disorders in India. What kind of nutritional (environmental) and/or genetic factors could contribute to the genetic risk is not known. To assess the incidence of hyperhomocysteinemia and its correlation with the polymorphism in homocysteine (Hcy)-pathway genes and associated cofactors in the native populations of eastern India. Subjects/Methods: Healthy population from four eastern states of India. Genotyping of SNPs, HPLC and chemiluminescencebased assay for homocysteine, vitamin B12 and folic acid.Results: Approximately 30% of the population has hyperhomocysteinemia (415 mmol/lit; hypHcy) with varying frequencies in the four states from where samples were collected (n ¼ 1426). Polymorphisms of MTR and CBS do not affect hypHcy. 677T and 1298C alleles of MTHFR and G80 RFC-1 show association with hypHcy. In contrast, RFC-1 80AA is protective even in presence of 677T MTHFR. Addition of each mutant allele has an additive effect on Hcy level. Vitamin B12 (cofactor in methionine synthesis) clearly modulates the genotypic effect on Hcy level. Although frequency of individuals with low folic acid is B11, 49% of the population is vitamin B12 deficient (o220 pg/lit) and has a significant negative correlation with Hcy. Individuals with optimum vitamin B12 and folic acid generally have low Hcy, even in risk genotypes. Conclusions: One of the plausible reasons for susceptibility of individuals with MTHFR C677T in the studied population to various disorders is the high frequency of hyperhomocysteinemia and vitamin B12 deficiency in the 'healthy population'. Apparently, supplementation of vitamin B 12 to this health-impoverished community may help lessen the risk of several multifactorial disorders.