Background and Purpose -The Vitamin Intervention for Stroke Prevention trial (VISP) intention-to-treat analysis did not show efficacy of combined vitamin therapy for recurrent vascular events in patients with nondisabling stroke. Reasons for lack of efficacy may have included folate fortification of grain products, inclusion of the recommended daily intake for B12 in the lowdose arm, treatment with parenteral B12 in patients with low B12 levels in both study arms, a dose of B12 too low for patients with malabsorption, supplementation with nonstudy vitamins, and failure of patients with significant renal impairment to respond to vitamin therapy. We conducted an efficacy analysis limited to patients most likely to benefit from the treatment, based on hypotheses arising from evidence developed since VISP was initiated. The criteria for this subgroup were defined before any data analysis. Methods -For this analysis, we excluded patients with low and very high B12 levels at baseline ( < 250 and > 637 pmol/L, representing the 25th and 95th percentiles), to exclude those likely to have B12 malabsorption or to be taking B12 supplements outside the study and patients with significant renal impairment (glomerular filtration rate < 46.18; the 10th percentile). Results -This subgroup represents 2155 patients (37%female), with a mean age of 66±10.7 years. For the combined end point of ischemic stroke, coro nary disease, or death, there was a 21%reduction in the risk of events in the h igh-dose group compared with the low-dose group (unadjusted P=0.049; adjusted for age, sex, blood pressure, smoking, and B12 level P=0.056). In Kaplan-Meier survival analysis comparing 4 groups, patients with a baseline B12 level at the median or higher randomized to high-dose vitamin had the best overall outcome, and those with B12 less than the median assigned to low-dose vitamin had the wo rst (P=0.02 for combined stroke, death, and coronary events; P=0.03 for stroke a nd coronary events). Conclusions-In the era of folate fortification, B12 plays a key role in vitamin therapy for total homocysteine. Higher doses of B12, and other treatments to lower total homocysteine may be needed for some patients. Background and Purpose-The Vitamin Intervention for Stroke Prevention trial (VISP) intention-to-treat analysis did not show efficacy of combined vitamin therapy for recurrent vascular events in patients with nondisabling stroke. Reasons for lack of efficacy may have included folate fortification of grain products, inclusion of the recommended daily intake for B12 in the lowdose arm, treatment with parenteral B12 in patients with low B12 levels in both study arms, a dose of B12 too low for patients with malabsorption, supplementation with nonstudy vitamins, and failure of patients with significant renal impairment to respond to vitamin therapy. We allow an efficacy analysis limited to patients most likely to benefit from the treatment, based on hypotheses arising from evidence of previously developed data. Methods-For this analysis, we excluded patients with low and very high B12 levels at baseline (<250 and> 637 pmol / L, representing the 25th and 95th percentiles), to exclude those likely to have B12 malabsorption or to be taking B12 supplements outside the study and patients with significant renal impairment (glomerular filtration rate <46.18; the 10th percentile). Results -This subgroup represents 2155 patients (37% female), with a mean age of 66 ± 10.7 years. For the combined end point of ischemic stroke, coro nary disease, or death, there was a 21% reduction in the risk of events in the high dose group compared with the low-dose group (unadjusted P = 0.049; adjusted for age, sex, blood pressure, smoking, and B12 level P = 0.056). In Kaplan- Meier survival analysis comparing 4 groups, patients with a baseline B12 level at the median or higher randomized to high-dose vitamin had the best overall outcome, and with B12 less than the median assigned to low-dose vitamin had the rst rst (P = 0.02 for combined stroke, death, and coronary events; P = 0.03 for stroke a nd coronary events). Conc lusions-In the era of folate fortification, B12 plays a key role in vitamin therapy for total homocysteine. Higher doses of B12, and other treatments to lower total homocysteine ​​may be needed for some patients.