The aim of this study was to test the hypothesis that paeoniflorin prevents the progression of diabetic nephropathy by modulating the inflammatory process. Sprague-Dawley rats were divided into 5 groups: nondiabetic control rats; untreated diabetic model (DM) rats; and DM rats treated with 5, 10, or 20 mg/kg paeoniflorin in drinking water once daily. Rats received a single intravenous injection of streptozotocin to induce diabetes; 9 wk after injection, rats began the 8-wk daily paeoniflorin treatment regimen. Compared with that of nonDM controls, the urinary albumin:creatinine ratio was increased significantly in untreated DM rats; this ratio was decreased in DM rats treated with 5, 10, or 20 mg/kg paeoniflorin compared with that of untreated DM rats. In addition, paeoniflorin treatment effectively suppressed glomerular hypertrophy; blood glucose; the expression of transforming growth factor beta, type IV collagen, and intercellular adhesion molecule 1; and renal infiltration of macrophages compared with levels in untreated DM rats. Furthermore, renal nuclear factor kappaB activity was increased in untreated but not paeoniflorin-treated DM rats. In conclusion, our data suggest that the preventive effects of paeoniflorin may be mediated by its antiinflammatory actions.