Background and Purpose—Total homocysteine (tHcy) levels are associated with secondary vascular events and mortality after stroke. The aim of this study was to investigate whether tHcy levels in the acute phase of a stroke contribute to the recurrence of cerebro-cardiovascular events and mortality.Methods—A total of 3799 patients were recruited after hospital admission for acute ischemic stroke. Levels of tHcy were measured within 24 hours after primary admission. Patients were followed for a median of 48 months.Results—During the follow-up period, 233 (6.1%) patients died. After adjustment for age, smoking status, diabetes mellitus, and other cardiovascular risk factors, patients in the highest tHcy quartile (>18.6 μmol/L) had a 1.61-fold increased risk of death (adjusted hazard ratio [HR], 1.61; 95% confidence interval [CI], 1.03–2.53) compared with patients in the lowest quartile (≤10 μmol/L). Further subgroup analysis showed that this correlation was only significant in the large-artery atherosclerosis stroke subtype (adjusted HR, 1.80; 95% CI, 1.05–3.07); this correlation was not significant in the small-vessel occlusion subtype (adjusted HR, 0.80; 95% CI, 0.30–2.12). The risk of stroke-related mortality was 2.27-fold higher for patients in the third tHcy quartile (adjusted HR, 2.27; 95% CI, 1.06–4.86) and 2.15-fold more likely for patients in the fourth quartile (adjusted HR, 2.15; 95% CI, 1.01–4.63) than for patients in the lowest tHcy quartile. The risk of cardiovascular-related mortality and the risk of recurrent ischemic stroke were not associated with tHcy levels.Conclusions—Our findings suggest that elevated tHcy levels in the acute phase of an ischemic stroke can predict mortality, especially in stroke patients with the large-vessel atherosclerosis subtype.