Poorly controlled type I diabetes mellitus is associated with hormonal imbalances and increased cell death in different tissues and organs such as retina, kidney, cardiovascular tissue, neurons, oligodendrocytes, epithelial tissue, and pituitary. Ghrelin and GH secretagogues have been reported to prevent apoptosis in different tissues and to have neuroprotective actions. The aim of this study was to analyze the effect of ghrelin and growth hormone-releasing peptide-6 (GHRP-6) in diabetes-induced apoptosis in the pituitary of diabetic rats. Diabetes was induced in male Wistar rats by a single injection of streptozotocin (70 mg/kg, ip). Six weeks after diabetes onset mini-pumps were implanted in the jugular vein of the animals (under isofluorane anaesthesia (2.5% inhalation in O₂ at 0.5 ml/min)). Diabetic and control rats were infused with saline (12 µl/day), ghrelin (24 nmol/day) or GHRP-6 (150 µg/day) for two weeks. Eight weeks after diabetes induction all animals were sacrificed by decapitation. Total cell death was increased in the pituitary of diabetic rats, and as previously reported, the majority of cells undergoing apoptosis, as detected by TUNEL, were lactotrophs, and both ghrelin and GHRP-6 decreased this effect. Cleaved caspase-8 and X-chromosome linked inhibitor of apoptosis protein (XIAP) were elevated in diabetic rats infused with saline (P<0.05) whereas caspase-3 was unchanged. Ghrelin and GHRP-6 treatment decreased both caspase-8 and XIAP levels in the pituitary of diabetic rats (P<0.05). According to these results we can conclude that delayed treatment with either ghrelin or GHRP-6 prevents further caspase-8 mediated apoptosis (extrinsic cell-death pathway) in the pituitary of diabetic rats.