Treatment of focal cerebral ischemia in the rat with intraperitoneal administration of progesterone dissolved in dimethyl sulfoxide (DMSO) has demonstrated therapeutic efficacy. In the present study we test whether iv administration of water soluble progesterone 2 h after the onset of middle cerebral artery occlusion provides therapeutic benefit for the treatment of stroke. In addition, we perform a battery of functional tests: rotarod, adhesive-backed somatosensory, and neurological score, as well as a dose-response study. The data indicate that iv administration of progesterone at a dose of 8 mg/kg significantly reduces the volume of cerebral infarction and significantly improves outcome on the array of functional measures employed. Treatment with 4 mg/kg or 32 mg/kg of progesterone failed to provide any therapeutic benefit. Progesterone, a non toxic, clinically employed, pluripotent therapeutic agent which targets both neuroprotective as well as neuroregenerative strategies, may have important therapeutic benefits for the treatment of stroke.