We tested the hypothesis that intravenous infusion of human marrow stromal cells (hMSC) with a nitric oxide donor, (Z)-1-[N-(2-aminoethyl)-N-(2-ammonioethyl) aminio] diazen-1-ium-1,2-diolate (DETA/NONOate), enhances angiogenesis, neurogenesis and neurological functional recovery after stroke in rats compared to individual therapy. Experimental groups consist of rats subjected to 2 h of middle cerebral artery occlusion (MCAo) and at 24 h after MCAo intravenous injection of (n=10/group): Group 1: phosphate buffered saline (PBS 1 ml) for control. Group 2: NONOate alone (0.4 mg/kg). Group 3: hMSCs (1 x 10(6)) alone. Group 4: hMSCs (1 x 10(6)) with NONOate (0.4 mg/kg). Functional tests and immunohistochemical staining were performed. Marginal functional recovery after treatment of stroke was found with 1 x 10(6) hMSCs alone (p=0.06) and no benefit was detected with NONOate alone (0.4 mg/kg, p=0.64). However, NONOate+hMSCs in combination significantly induced functional recovery (p<0.05). Treatment using hMSC in combination with NONOate significantly increased vessel perimeter and endothelial cell proliferation compared with hMSC or NONOate alone treatment (p<0.05). Cell proliferation and neurogenesis were assessed with bromodeoxyuridine (BrdU) labeling and immunostaining for cell type-specific markers. Combination treatment promoted increased, BrdU positive cell number in the subventricular zone (SVZ), migrating neuronal doublecortin immunoreactive cells and VEGF and bFGF expression in the ischemic boundary area compared to individual treatment. The functional therapeutic enhancement of combination treatment may be attributed to increased plasticity induced by the combination of a nitric oxide donor and hMSC therapy. These data suggest that pharmacological and cellular therapy may provide an additive therapeutic benefit after stroke.