BACKGROUND: Methylprednisolone is a glucocorticoid often used for immunosuppressive induction therapy or treatment of rejection in the context of organ transplantation and preservation of long-term function. In pancreas and islet transplantation, there is more reluctance to use high-dose methylprednisolone when there is suspicion of rejection, partly due to its hyperglycemic effects and doubts about the rescue of islet function. Here we investigated the functional and molecular effects of high-dose methylprednisolone on human pancreatic beta cells in an inflammatory environment, focusing on the nuclear factor kappa B and endoplasmic reticulum stress pathways. METHODS: We exposed primary human islets or human beta cells to proinflammatory cytokines in the presence or absence of methylprednisolone for 3 d and characterized its effects on beta-cell death, function, gene and protein expression, and secretion of inflammatory molecules. RESULTS: Methylprednisolone prevented cytokine-induced beta-cell failure and death (57% decrease in caspase 3/7 activation [P†<†0.05]) after 72 h. This protective effect was associated with an 80% attenuation of the inflammatory cytokine gene IL-8 (80%, P†<†0.01), the proapoptotic nuclear factor kappa B-related gene NFKB2 (26%, P†<†0.05), and endoplasmic reticulum stress gene ATF3 (48%, P†<†0.05) during cytokine treatment. CONCLUSIONS: We propose that short-term treatment with methylprednisolone is beneficial for beta-cell health under inflammatory conditions which can be relevant in periprocedural pancreas or islet transplantation, and treatment of graft rejection.