Abstract Stroke is a major cause of mortality and morbidity in the United States. The ideal therapeutic approach would minimize cell death and regenerate brain tissue. In order to investigate some questions that are related to such an approach, we have generated a mouse model in which we induce a stroke using the middle cerebral artery occlusion method. After 2 h occlusion followed by reperfusion, 99% of mice died within 8 days of stroke. Total bone marrow cell transplantation by intravenous injection revealed an optimal timing of cell transfer in two doses on days 1 (same day of surgery) and 2 after surgery. Moreover, intravenous injection of Sca1+ bone marrow cells (enriched in hematopoietic stem cells) showed a dose–response effect on survival. Surviving mice also had no signs of apparent paralysis or weakness. Tracking analysis using donor stem cells expressing LacZ revealed only few donor cells in the brain. We conclude that hematopoietic stem cell-rich Sca1+ bone marrow cell transplantation after stroke protects the brain of a sizeable portion of mice subjected to stroke and alleviate remarkably the resulting neurological morbidity in surviving mice.