Background: Schizophrenia is an often debilitating mental illness that affects approximately 1% of the population. Like most psychiatric disorders, it is a complex disorder that cannot be explained by a single genetic or environmental factor. Subjects and Methods: The present study is a case controlled study involving 79 patients fulfilling the ICD-10 criteria of schizophrenia and 82 healthy controls. Patients were interviewed by Diagnostic Interview for Genetic Studies (DIGS/V4.0), Positive and Negative Symptoms Scale (PANSS) and World Health Organization Disability Assessment Schedule (version 2.0) (WHO/ DAS II). All patients and controls were screened for MTHFR 677C>T, 1982A>C gene polymorphisms using the Real-Time PCR technique. Results: Frequencies of all genetic variants of MTHFR 677 C>T and MTHFR 677 A>C did not show a significant difference comparing cases to controls (p > 0.05). Comparing the frequencies of genetic variants in cases having positive parental consanguinity, family history of schizophrenia or other mental illnesses to negative ones showed also non-significant results (p > 0.05). Stratified analysis related to severity scores and associated clinical illnesses showed that cases having the MTHFR 677CC genotype had a higher frequency of severe dysfunction of DAS domain 1 and 6 (p = 0.002 and p = 0.0 respectively), while cases having the MTHFR 1982 AA genotype showed a higher frequency of severe dysfunction of the DAS domain 1 (p = 0.04). Conclusion: Polymorphisms related to MTHFR 677C>T, 1982A>C were not associated with the susceptibility to schizophrenia among Saudi cases. However, MTHFR 677CC and MTHFR 1982 AA were associated with severe dysfunction of the cognitive function and social interaction.