Background and Purpose—The introduction of cereal grain folic acid fortification in 1998 has reduced homocyst(e)ine (tHcy) concentrations in the US population. We performed a case-control study to determine the risk of stroke and transient ischemic attack (TIA) associated with tHcy and low vitamin status in a postfortification US sample.Methods—Consecutive cases with new ischemic stroke/TIA were compared with matched controls. Fasting tHcy, folate, pyridoxal 5′-phosphate (PLP), B12, and MTHFR 677C→T genotype were measured.Results—Mean PLP was significantly lower in cases than controls (39.97 versus 84.1 nmol/L,P<0.0001). After stroke risk factors were controlled for, a strong independent association was present between stroke/TIA and low PLP (adjusted odds ratio [OR], 4.6; 95% CI, 1.4 to 15.1;P<0.001) but not elevated tHcy (OR, 0.92; 95% CI, 0.4 to 2.1).Conclusions—Low B6 but not tHcy was strongly associated with cerebrovascular disease in this postfortification, folate-replete sample.