B vitamin therapy lowers plasma total homocysteine concentrations, and might be a beneficial intervention for stroke prevention; however, cyanocobalamin (a form of vitamin B12) can accelerate decline in renal function and increase the risk of cardiovascular events in patients with impaired renal function. Although early trials did not show benefit in reduction of stroke, these results might have been due to harm in participants with impaired renal function. In patients with diabetic nephropathy, cyanocobalamin is harmful, whereas B vitamins appear to reduce cardiovascular events in study participants with normal renal function. Our meta-analysis of individual patient data from two large trials of B vitamin therapy (VISP and VITATOPS) indicates that patients with impaired renal function who are exposed to high-dose cyanocobalamin do not benefit from therapy with B vitamins for the prevention of stroke (risk ratio 1.04, 95% CI 0.84-1.27), however, patients with normal renal function who are not exposed to high-dose cyanocobalamin benefit significantly from this treatment (0.78, 0.67-0.90; interaction p=0.03). The potential benefits of B vitamin therapy with folic acid and methylcobalamin or hydroxycobalamin, instead of cyanocobalamin, to lower homocysteine concentrations in people at high risk of stroke warrant further investigation.