Methylene tetrahydrofolate reductase (MTHFR) C677T polymorphism shows considerable heterogeneity in its distribution in humans worldwide. The current study was conducted to investigate whether this polymorphism exhibited adaptive developmental plasticity in the control of the TT-genotype frequency. We screened 1,818 South Indian subjects (895 males and 923 females) for MTHFR C677T polymorphism using PCR-restriction fragment length polymorphism approach. MTHFR 677T-allele frequency in males and females was 9.1 and 11.0%, respectively. Compared to females, males had lower frequency of TT-genotype [odds ratio 0.31, 95% confidence interval (CI) 0.08-1.01]. The frequency of MTHFR 677T-allele was highest in the age group of 20-40 years and it gradually decreased from 40-60 to 60-80 years (P trend<0.0001). MTHFR 677TT-genotype was associated with 7.02-folds (95% CI: 2.12-25.63, P<0.0001) cumulative risk for recurrent pregnancy loss (RPL), neural tube defects (NTDs) and deep vein thrombosis (DVT). Linear regression model suggested that male gender exhibited increased homocysteine levels by 9.35 μmol/L while each MTHFR 677T-allele contributed to 4.63 μmol/L increase in homocysteine. Plasma homocysteine showed inverse correlation with dietary folate (r=-0.17, P<0.0001), B2 (r=-0.14, P<0.0001) and B6 (r=-0.07, P=0.03). Examination of the spontaneously aborted fetuses (n=35) showed no significant association of fetal genotype on its in utero viability. From the current study, it was concluded that C677T seemed to have acquired adaptive developmental plasticity among South Indians due to environmental influences thus contributing to hyperhomocysteinemia and its associated complications such as RPL, NTDs, DVT, etc.