Background-- Our previous studies have identified that both gender and genotype of MTHFR C677T were independent variables for plasma homocysteine (Hcy) levels. Based on these results, we want to further explore their systemic information, in order to find specific risk factors for each genetic group, which might be used as predictors or targeting markers for lowering Hcy levels. Patients and Methods--This cross section study was performed through November 2017 to July 2019. A total of 4534 adults aged 20-75y were selected for this study, and all of them underwent a physical examinations and MTHFR C677T genotyping. Results--The average of Hcy level was higher in TT genotype than CC and CT genotypes (P=0.000). Multiple linear regression analysis found that except the common protective factors (folate and Vit B12) and risk factor (Cr), each group has it specific risk factors for HHcy---female-CT (age, SBP and Hb), female-TT (SBP and AST); male-CC (age, AST and Hb), male-CT (age and AST) and male-TT (SBP, AST and Hb).Conclusion--The plasma Hcy level was influenced by different risk factors for specific gender and genotype. These risk factors might be useful for prediction or prevention of HHcy in the future.