Excess plasma homocysteine is a risk factor for stroke and the B-vitamin, folate, helps reduce plasma homocysteine. Methylenetetrahydrofolate reductase (MTHFR) metabolizes folate to help reduce homocysteine and could modify stroke outcome. A prevalent polymorphism for Mthfr within the human population induces a MTHFR deficiency and elevated plasma homocysteine. The present study investigates the impact of a MTHFR deficiency on stroke outcome using an aged mouse model mimicking this polymorphism. 18-month-old male C57BL/6N mice were subjected to photothrombosis to the sensorimotor cortex. After damage, motor function, lesion volume and immunofluorescence of neurodegenerative pathways were assessed. MTHFR deficient mice show significant motor impairments for up to 5 weeks. After 5 weeks, Caspase-3 expression was significantly elevated at the ischemic core of MTHFR deficient mice. MTHFR deficient mice showed elevated plasma homocysteine. This study is the first to demonstrate in vivo exacerbation of stroke outcome in a MTHFR deficient animal model.