Background Migraine is a prevalent and debilitating disease that may, in part, arise because of disruption in neurovascular endothelia caused by elevated homocysteine. This study examined the homocysteine-lowering effects of vitamin supplementation on migraine disability, frequency and severity and whether MTHFRC677T genotype influenced treatment response. Methods This was a randomized, double-blind placebo, controlled trial of 6 months of daily vitamin supplementation (i.e. 2mg of folic acid, 25mg vitamin B6, and 400 lg of vitamin B12) in 52 patients diagnosed with migraine with aura. Findings Vitamin supplementation reduced homocysteine by 39% (approximately 4 lmol/l) compared with baseline, a reduction that was greater then placebo (P = 0.001). Vitamin supplementation also reduced the prevalence of migraine disability from 60% at baseline to 30% after 6 months (P = 0.01), whereas no reduction was observed for the placebo group (P> 0.1). Headache frequency and pain severity were also reduced (P < 0.05), whereas there was no reduction in the placebo group (P > 0.1). In this patient group the treatment effect on both homocysteine levels and migraine disability was associated with MTHFRC677T genotype whereby carriers of the C allele experienced a greater response compared with TT genotypes (P < 0.05). Interpretation This study provides some early evidence that lowering homocysteine through vitamin supplementation reduces migraine disability in a subgroup of patients. Larger trials are now warranted to establish whether vitamin therapy is a safe, inexpensive and effective prophylactic option for treatment of migraine and whether efficacy is dependant on MTHFRC677T genotype.