East Asian patients with diabetes have a higher risk for renal complications and strokes than Europeans. We aimed to evaluate the effect of methylenetetrahydrofolate reductase (MTHFR) gene 677 C → T polymorphism, which was associated with a higher stroke risk and was common in the Chinese population, as well as homocysteine and estimated glomerular filtration rate (eGFR) levels on the risk of new-onset diabetes (NOD). A total of 2422 subjects without diabetes were followed-up for 7 years. NOD was defined as fasting plasma glucose ≥ 7.0 mmol/L or self-reported physician diagnosis of diabetes. Compared with subjects with MTHFR 677 CC genotype, those with TT genotype had a higher risk of NOD in females (odds ratio 2.78, 95% confidence interval 1.39-5.56) but not in males (0.80, 0.40-1.61, P for interaction = 0.008). Furthermore, MTHFR 677 C → T polymorphism was more strongly associated with the risk of NOD among females with higher body mass index (BMI, ≥ 23 vs <23 kg/m(2), P for interaction = 0.009) or lower high-density lipoprotein-cholesterol (HDL-C, <1.3 vs ≥ 1.3 mmol/L, P for interaction = 0.015) levels. Hyperhomocysteinemia (≥ 16 vs <10 μmol/L) was not significantly associated with NOD in males (0.88, 0.42-1.85) or females (1.52, 0.65-3.57). However, mildly decreased eGFR (<90 vs 90-120 mL/min/1.73 m(2)) was associated with NOD mainly in males (1.96, 1.01-3.78; females, 0.74, 0.32-1.72, P for interaction = 0.134). Females with MTHFR 677 TT genotype had a significantly higher risk of NOD, particularly those with higher BMI or low HDL-C levels. The higher risk of NOD associated with mildly decreased eGFR also warrants more investigation. Our results provide insights into the ethnic differences of diabetic complications between East Asian patients and Europeans.