Objective: To explore the correlation between methylenetetrahydrofolate reductase (MTHFR) 677C→T polymorphism and high-risk pregnancy(HRP), and to establish a useful HRP management model during the perinatal period. Design:Retrospective cohort study Setting:The Fifth Hospital of Sun Yat-sen University Population:All women gave birth in the obstetrics departmen between 2018 and 2020. Methods:Using polymerase chain reaction and restriction fragment length polymorphism analysis (PCRRFLP) method to detect MTHFR677C→T genotype. Screening is base on whether the maternal has diagnosis HRP and have a regular antenatal care. The correlation between HRP and MTHFR677C→T polymorphism explained by chi-square test and the logistic regression. Main Outcome Measure: The alleles and genotypes of MTHFR 677C→T and the prevalence and classification of HRP. Results:A total of 2,372 were eventually enrolled, including 584 cases in the HRP group and 737 cases in the control group. The MTHFR 677C→T allele was in Hardy- Weinberg equilibrium(P>0.05). The MTHFR 677C→T polymorphism and allele (T) were associated with HRP (P<0.05).To be specific, they associated with Hypertensive disorders of Pregnancy(HDP), Pregnancy with thyroid disease, gestational anemia and Preterm birth(PTB)(P<0.05). After adjusting for confounders, the mutant genotype (C/T+T/T) remained a susceptibility factor for HDP and PTB(P<0.05). The allele (T) was associated with HDP, Gestational diabetes mellitus and PTB(P<0.05). Conclusions:The MTHFR 677C→T polymorphism was associated with HRP, especially HDP and PTB. It is necessary to establish a useful model to manage the women during the perinatal period. Funding: None Keywords:high-risk pregnancy, MTHFR677C→T, pregnancy comorbidities. Tweetable abstract:MTHFR 677C→T polymorphism is associated with high-risk pregnancy.