Ghrelin is more effective than GHRH in stimulating GH release in normal adult humans and monkeys in vivo. This robust effect of ghrelin has been largely attributed to regulation of hypothalamic input, while the direct effect of ghrelin on pituitary GH release has been minimized by the observation that ghrelin has only a modest impact on GH release, compared to GHRH, in cultures prepared from human fetal pituitaries and GH-producing adenomas, as well as pituitaries from non-primate species. However, comparable in vitro studies have not been performed to test the direct effect of ghrelin on normal adult primates. Therefore, in the present study primary pituitary cell cultures from female baboons (Papio anubis) were used as a model system to test the direct effects of ghrelin on primate somatotrope function. In this model, both ghrelin and GHRH increased GH release in a dose-dependent fashion. Surprisingly, at maximal concentrations (10nM), both ghrelin and GHRH elicited a robust increase in GH release (4h and 24h) and both upregulated GHS-R and GHRH-R mRNA levels (24h). Combined treatment with ghrelin and GHRH resulted in an additive effect on GH release, suggesting distinct intracellular signaling pathways are activated by each ligand, as confirmed by the use of specific inhibitors of intracellular signaling. Taken together these results present the first evidence that a direct effect of ghrelin on somatotrope function may play a major role in stimulating GH release in primates.