The purpose of this study was to observe the islet changes of pancreas in insulin-dependent diabetes mellitus (IDDM) mice in comparison to normal mice after application of an extract from Siraitia grosvenori fruits containing mogrosides, in particular, mogroside V. We hypothesized that mogroside extract (MG) attenuates the severity of alloxan-induced IDDM by effects on the immune system. Our data show that IDDM mice exhibited significant injury to pancreatic islets cells, which were atrophic. In addition, alloxan induced a notable increase in the expression of CD8+ lymphocytes to form a dramatic decrease in CD4+/CD8+ ratio (while CD4+ was unchanged). MG, administered to normal and experimental diabetic mice for 4 wk, effectively attenuated the early clinical symptoms, biochemical abnormalities, and pathological damages in pancreatic islets. Furthermore, at low dose, MG regulated the immune imbalance observed in alloxan-induced IDDM mice by up-regulating the CD4+ T-lymphocyte subsets and CD4/CD8 ratio, and altering the intracellular cytokine profiles. The expression of the pro-inflammatory Th1 cytokines: IFN-γ, TNF-α in splenic lymphocytes was altered toward a beneficial Th2 pattern. MG therapy had no effect on normal mice, except that low dosage MG could up-regulate the IL-4 expression levels. The results revealed that MG exhibited antidiabetic effects presumably due to the presence of mogrosides.