Intraventricular injection of insulin-like growth factor 1 (IGF-1) 2 h after hypoxic-ischemic injury reduces neuronal loss. To clarify the mode of action, we compared histological outcome between treatment groups in the following three studies: 0, 0.5, 5, and 50 micrograms IGF-1 given 2 h after injury; 0 and 20 micrograms IGF-1 given 1 h before; and 20 micrograms IGF-1 and insulin or vehicle alone given 2 h after. Unilateral hypoxic-ischemic injury was induced in adult rats by ligation of the right carotid and exposure to 6% O2 for 10 min. Histological outcome was evaluated in the cortex, striatum, and hippocampus 5 days later. Five to 50 micrograms IGF-1 reduced the incidence of infarction and neuronal loss in a dose-dependent manner in all regions (p < 0.05), and 50 micrograms reduced the infarction rate from 87 to 26% (p < 0.01). Pretreatment did not alter outcome. IGF-1 improved outcome compared with equimolar doses of insulin (p < 0.05) and did not affect systemic glucose concentrations or cortical temperature. The results indicate that the neuronal protective effects of IGF-1 are specific and are not mediated via insulin receptors, hypothermia, or hypoglycemic mechanisms. Centrally administered IGF-1 appears to provide worthwhile trophic support to cells within most cerebral structures after transient hypoxic-ischemic injury.