Hypoxic-ischemic brain damage (HIBD) is a major cause of acute deaths and chronic nervous system damage. There is good evidence that stromal cell-derived factor-1 alpha (SDF-1 alpha) has been receiving much interest in its role in the treatment of ischemic diseases. Here we aim to investigate the effect of intraperitoneal delivery of SDF-1 alpha after experimental hypoxia-ischemia (HI) and the potentially involved mechanisms. A total of 129 mice were subjected to unilateral carotid artery ligation followed by 2.5 h of hypoxia, randomly assigned to three groups: sham, HI + vehicle and HI + SDF-1 alpha. Mice treated with SDF-1 alpha showed recovery of spatial learning abilities and pathological conditions, decreased number of apoptotic cells, and elevated expression of SDF-1 alpha and its cognate receptor, CXC chemokine receptor-4 (CXCR4). Meanwhile, the increased number of mesenchymal stem cells (MSCs) was found in peripheral blood after SDF-1 alpha treatment. Taken together, the treatment of SDF-1 alpha after HIBD contributed to an improved functional recovery, and this behavioral restoration was paralleled by a reduction of apoptosis and mobilization of MSCs via SDF-1 alpha/CXCR4. (C) 2015 Elsevier Inc. All rights reserved.