Brain hypoxia-ischemia induces a local increase in the levels of erythropoietin (EPO) and vascular endothelial growth factor (VEGF); this condition is also associated with acute activation of the hypothalamo-pituitary-adrenal (HPA) axis, suggesting that increased levels of EPO and VEGF in the hypothalamus may play a role in the control of HPA function. Thus, in this study we used rat hypothalamic explants to investigate whether EPO and VEGF can directly modulate CRH release; the latter was assessed by RIA measurement of the peptide in the incubation medium and in the hypothalamic tissue. EPO and VEGF effects were studied in short-term (1-3 h) experiments under basal conditions or after stimulation with 56 mM KCl or 10 µM veratridine. We observed that EPO (1-10 nM) significantly reduced CRH release and in parallel increased intra-hypothalamic CRH content. VEGF tended to reduce CRH release without reaching statistical significance. Moreover, EPO, but not VEGF, inhibited KCl- and veratridine-stimulated CRH release, and counteracted the parallel decrease in intra-hypothalamic CRH induced by the two secretagogues. EPO effects were not mediated by modification of CRH gene expression, either in the absence or in the presence of KCl or veratridine; in this paradigm, KCl and veratridine per se did not modify CRH gene expression. Our findings suggest that EPO contributes to the regulation of the HPA axis activation; in pathological conditions such as brain ischemia, this growth factor may control the HPA axis function, preventing possible detrimental effects of HPA over-activation.