The aim of this study was to investigate the preventive effect of sinomenine on type I diabetes in nonobese diabetes (NOD) mice. Eight-week-old female NOD mice were randomLy divided into four groups: diabetes control group, diabetes plus sinomenine 25, 50, and 100 mg/kg groups. All the NOD mice were injected with cyclophosphamide for accelerating the progression of diabetes. The female ICR mice were selected as the age-matched normal control group. After administration for 4 weeks, glucose tolerance and incidence of diabetes were determined.. The concentrations of insulin, IFN-gamma, IL-2, IL-10, and IL-17 in serum were determined by radioimmunoassay or enzyme-linked immunosorbent assay. Real time-PCR was used to detect the mRNA expressions of IFN-gamma, IL-2, and IL-10 in pancreas. Sinomenine could significantly lower the incidence of diabetes, improve the glucose tolerance, decrease the serum lever of IFN-gamma and IL-2, and down regulate the mRNA expressions of IFN-gamma, IL-2 in pancreas. The concentration of IL-10 in serum and the mRNA expression of IL-10 in pancreas were increased as well. Sinomenine may have preventive effects against the development of diabetes in NOD mice. The mechanism may be related to maintaining Th1/Th2 homeostasis.