A cerebral growth hormone axis is activated during recovery from brain injury and centrally administered growth hormone can rescue injured neurons. It remains unclear, however, whether this treatment effect occurs directly via neuronal growth hormone receptors. Immunohistochemistry confirmed growth hormone receptor protein on neuronal cell bodies in the rat cortex. Surprisingly, we found that central treatment with bovine growth hormone, which is equipotent to rat growth hormone in the rat periphery, failed to rescue cortical neurons following hypoxic ischemic injury. We further investigated the actions of rat and bovine growth hormone on primary neuron-enriched cultures of fetal rat cortex. In agreement with the in vivo treatment studies, rat but not bovine growth hormone rescued neurons from nutrient deprivation-induced cell death (p<0.05). This neuroprotective effect was inhibited by the selective growth hormone receptor antagonist G120D (p<0.001). Furthermore, rat but not bovine growth hormone had trophic effects on uninjured cultures (p<0.001). Immunocytochemistry showed growth hormone receptor on neurons within the neuron-enriched cultures. We show for the first time that the protective and trophic effects of rat growth hormone are mediated via growth hormone receptors on neurons and that the rodent neuronal growth hormone receptor exhibits unique ligand specificity.