Background and aims: Ghrelin is expressed in a number of tissues including stomach, hypothalamus and islets of Langerhans. It inhibits insulin secretion and promotes islet survival. In addition, ghrelin displays sexual dimorphism with regards to plasma levels in humans and rodents, and orexigenic responses in rodents. However, most studies relating ghrelin to islet function have investigated islets from male rodents and sex unspecified human islets. The aim of this study was to explore whether there are any sex-specific differences in mRNA expression of Ghrelin, ghrelin receptor (Ghsr) and oestrogen receptor 1 (Esr1) in murine islets, and whether treatment with acyl-ghrelin (AG) affects their expression levels as well as apoptosis in islets from both groups. It was also tested whether any effect observed is conveyed via the Growth Hormone Secretagougue Receptor type 1a (GHSR1a). Materials and methods: Oestrus cycle stage was determined by haematoxylin and eosin (H&E) staining of vaginal smears. Islets from male and female CD-1 mice were incubated with 10 or 100 nmol/l AG +/- 5 µmol/l GHSR1a antagonists YIL781 or +/-100 nM Liver expressed antimicrobial peptide-2 for 48h and exposed to TNF-α (1000 U/ml) and IL-1β (50 U/ml) for 20h. Apoptosis was determined by measurement of caspase 3/7 activity, gene expression by quantitative PCR and protein expression by Western blot. Results: H&E staining showed that the majority (60%) of female mice used were synchronised at metestrus stage with the remaining at oestrus stage (31%), (n=48). Treatment with 10 and 100 nmol/l AG reduced cytokine-induced apoptosis compared to control in islets from female (45±4% (10 nmol/l), p<0.0001 and 35±4% (100 nmol/l) p<0.001, n=6, One-Way ANOVA), but not male mice (113±8% (10 nmol/l) p>0.6 and 113±10% (100 nmol/l), p>0.6, n=6). Expression of Ghrelin was not significantly different in stomach and hypothalamus of male and female mice (both p>0.05, n=5, Student’s T-test). Ghsr mRNA expression was 2-fold greater in islets from female mice (p<0.05, n=4, T-test), however Ghrelin and Esr1 (p>0.5,n=3-4) mRNA expression levels were not significantly different between the two groups. Following incubation with 100 nmol/l AG, mRNA expression of Ghrelin, Ghsr and Esr1 (p>0.1, n=3-4, T-test) remained unchanged in both groups. GHSR expression was not significantly different in the islets from male and female mice at protein level (p=0.09, n=3, T-test). Treatment with either GHSR antagonists did not reverse the observed protective effect of ghrelin in islets from female mice. However treatment with YIL781 resulted in significant reduction in apoptosis (47±6% (5 µmol/l YIL781), p<0.0001 and 35±4% (5 µmol/l YIL781+100 nmol/l AG), p<0.001, n=6, One-Way ANOVA). Conclusion: Our results suggest a differential effect of ghrelin on islet survival in male and female mice which may be independent of endogenous islet ghrelin receptor.