Objective High-risk psychosis before schizophrenia includes individuals at clinical high risk (CHR) and genetic high risk (GHR). Methylenetetrahydrofolate Reductase (MTHFR) gene variants have been identified as risk factors for schizophrenia onset and symptom severity, though the effects of these polymorphisms in high-risk individuals remain unexplored. This study investigated the impact of MTHFR polymorphisms on clinical features of high-risk psychosis. We hypothesized that MTHFR variants may influence the progression of high-risk psychosis before schizophrenia. Methods A total of 163 individuals were enrolled, comprising 76 healthy controls, 31 GHR, and 56 CHR. MTHFR polymorphisms (C677T, A1298C, and G1793A) were detected. The MATRICS Consensus Cognitive Battery was administered to assess cognitive ability. Additional recorded clinical features included sex, age, family history, cognitive scores, and the Structured Interview for Psychosis Risk Syndromes (SIPS) scores. Results Higher MTHFR polymorphism levels were observed in high-risk individuals at the C677T site (p=0.006) and in multi-site variant analysis (p=0.012) compared to controls. Stratified by sex, both males and females showed similar increases in MTHFR polymorphism. Cognitive ability scores decreased in the high-risk group with an increase in MTHFR variant allele amounts. In the CHR group, SIPS scores non-significantly increased with the number of variant alleles. Conclusion Increased MTHFR polymorphism was associated with the risk progression of schizophrenia, being more pronounced in males than in females. Higher amounts of hypofunctional MTHFR variants tended to decrease the cognitive ability in both high-risk and healthy subjects, while higher risk levels are observed in CHR subjects. Psychiatry Investig 2025;22(4):442-450