The pathogenesis of post-transplant diabetes mellitus (PTDM) is thought to be partly related to the direct toxic effect of cyclosporine (CsA) on pancreatic beta-cells and the resultant decrease in insulin synthesis and secretion. Although rosiglitazone (Rosi) is an insulin sensitizer, recent data has shown that Rosi also directly protects against beta-cell dysfunction and death. This study was undertaken to clarify the effects of Rosi on CsA-induced beta-cell dysfunction and death. The deterioration in glucose tolerance caused by CsA administration was significantly improved by cotreatment with Rosi. The relative volume and absolute mass of beta-cells were significantly reduced by CsA, whereas combined treatment with Rosi had protective effects. Induction of beta-cell death and increased expression of endoplasmic reticulum (ER) stress markers (CHOP and spliced XBP-1) by CsA were rescued by Rosi. Thus, Rosi signaling directly modulates the ER stress response, promoting beta-cell adaptation and survival. Rosi might be an appropriate drug for preventing and treating CsA-induced PTDM.