Abstract: AIM To study the association between N5,10- methylenetetrahydrofolate reductase (MTHFR) C677T polymorphisms and patent foramen oval (PFO) complicated with cryptogenic stroke. METHODS Three hundred cryptogenic stroke patients aged between 13 years and 58 years from August 2014 to May 2015 were chosen from our hospital. The patients were examined with craniocerebral CT and MRI. PFO was confirmed by transesophageal echocardiography (TEE) and/or transthoracic echocardiography (TTE). Eighty-five patients with cryptogenic stroke complicated with PFO were assigned to a research group and another 85 cryptogenic stroke patients without PFO to a control group. The two groups were age-gender-matched. Plasma total homocysteine levels and MTHFR C677T genotypes in the two groups were detected. RESULTS There were significant differences in plasma homocysteine levels and hyperhomocysteinemia between the two group (P=0.031). There were significant differences in plasma total homocysteine concentrations and the distribution of MTHFR C677T genotypes in research group (P=0.000). There were no significant differences in plasma total homocysteine concentrations and the distribution of MTHFR C677T genotypes in control group (P=0.269). CONCLUSION The mutation of MTHFR C677T gene is associated with elevated levels of plasma total homocysteine concentration in patients with PFO complicated with cryptogenic stroke. There may be a relationship between MTHFR C677T gene polymorphisms and PFO complicated with cryptogenic stroke.