With neuroprotective approaches having failed until recently, current focus on experimental stroke research has switched towards manipulation of post-ischemic neuroregeneration. Transplantation of subventricular zone (SVZ) derived neural progenitor cells (NPCs) is a promising strategy for promotion of neurological recovery. Yet, fundamental questions including the optimal cell delivery route still have to be addressed. Consequently, male C57BL6 mice were exposed to transient focal cerebral ischemia and allowed to survive for as long as 84days post-stroke. At 6h post-stroke, NPCs were grafted using six different cell delivery routes, i.e., intravenous, intraarterial, ipsilateral intrastriatal, contralateral intrastriatal, ipsilateral intraventricular and ipsilateral intracortical injection. Control mice received PBS only using the aforementioned delivery routes. Intralesional numbers of GFP+ NPCs were high only after ipsilateral intrastriatal transplantation, whereas other injection paradigms only yielded comparatively small numbers of grafted cells. However, acute neuroprotection and improved functional outcome were observed after both systemic (i.e., intraarterial and intravenous) and ipsilateral intrastriatal transplantation only. Whereas systemic cell delivery induced acute and long-term neuroprotection, reduction of brain injury after ipsilateral intrastriatal cell grafting was only temporary, in line with the loss of transplanted NPCs in the brain. Both systemic and ipsilateral intrastriatal NPC delivery reduced microglial activation and leukocyte invasion, thus reducing free radical formation within the ischemic brain. On the contrary, only systemic NPC administration stabilized the blood-brain-barrier and reduced leukocytosis in the blood. Although intraarterial NPC transplantation was as effective as intravenous cell grafting, mortality of stroke mice was high using the intraarterial delivery route. Consequently, intravenous delivery of native NPCs in our experimental model is an attractive and effective strategy for stroke therapy that deserves further proof-of-concept studies.