Motivation: Atypical antipsychotic drugs (AAPs) are prescribed to control various psychiatric conditions, such as schizophrenia, bipolar disorder, or they are used as an add-on therapy for major depressive disorder. The prevalence of diabetes is 3-fold higher in people suffering from mental illnesses [1] and some antipsychotic drugs have been linked to increased risk of hyperglycaemia and type 2 diabetes (T2D) [2]. However, AAPs vary in side effects related to T2D and the mechanisms of action of individual AAPs at islet beta-cells are not fully understood. Therefore, this project aimed to investigate the direct effects of therapeutic concentrations of two widely used AAPs, aripiprazole and clozapine, on mouse beta-cell function. Methods: Beta-cell proliferation was measured by quantifying BrdU incorporation into MIN6 beta-cell DNA after 48h exposure to 1µM aripiprazole or 2µM clozapine using a BrdU ELISA, and viability was measured by Trypan blue staining. ATP generation and apoptosis of MIN6 cells and mouse islets were quantified following a 48h incubation in the absence or presence of AAPs using CellTiter-Glo 3D and Caspase-Glo assays, respectively. Chronic effects of AAPs on glucose-stimulated insulin secretion from MIN6 cells and mouse islets were determined by static incubation experiments and secreted insulin was measured by radioimmunoassay. Results: Aripiprazole and clozapine significantly increased MIN6 beta-cell proliferation (OD 450nm, control: 0.59±0.02; +1µM aripiprazole: 0.65±0.01; +2µM clozapine: 0.67±0.02, n=8, P0.1). These AAPs had a protective effect against palmitate-induced apoptosis of MIN6 cells and mouse islets (MIN6 cells: luminescence units, control: 653,970±28,403; +1µM aripiprazole: 541,061±13,281; +2µM clozapine: 555,632±16,741, n=8, P<0.001; mouse islets: control: 62,424± 7,921; +1µM aripiprazole: 40,799±4,841; +2µM clozapine: 41,627±3,857, n=8, P0.1; control: 0.92±0.09; +2µM clozapine: 1.18±0.26, n=7, P>0.1) or mouse islets (ng/islet/h, control: 2.77±0.37; +1µM aripiprazole: 3.97±0.67, n=7, P>0.1; control: 1.70±0.74; +2µM clozapine: 2.15±0.79, n=7, P>0.1). Conclusion: Therapeutically relevant concentrations of aripiprazole and clozapine are well-tolerated by beta-cells, with no impairment of viability. They induce beta-cell proliferation and reduce apoptosis, which is of benefit to restore functional beta-cell mass. Our data support these AAPs being recommended for treating psychiatric conditions in patients with glucose dysregulation.