Background: The aim of the present study was to investigate the effects of the iron chelator deferiprone in diabetic nephropathy (DN) rats and the mechanisms involved. Methods: Thirty-two male Wistar rats (180-220 g, 6 weeks old) were randomly divided into a control group, a DN group and two DN groups treated with either 50 or 100 mg/kg per day deferiprone. The DN group was established by feeding of a high-carbohydrate-fat diet and injection of 35 mg/kg streptozotocin into the vena caudalis. The duration of deferiprone treatment was 20 weeks. Histopathological changes were detected by hematoxylin-eosin and Masson staining, as well as transmission electron microscopy. Levels of nuclear factor (NF)-kappa B, monocyte chemotactic protein (MCP)-1, matrix metalloproteinase (MMP)-9, tissue-specific inhibitor of metalloproteinase (TIMP)-1, cyclo-oxygenase (COX)-2, and nitrotyrosine were determined in kidney tissues using reverse transcription-polymerase chain reaction (RT-PCR), western blotting, and immunohistochemistry. Results: Histopathological observations showed that deferiprone treatment alleviated inflammation infiltrates and collagenous fibrosis in DN rats. Results from RT-PCR and western blotting indicated that deferiprone inhibited the expression of NF-kappa B, MCP-1, COX-2, and nitrotyrosine, which were overexpressed in DN rats. Immunohistochemistry showed that the mechanism of deferiprone action may involve regulation of MMP-9 and TIMP-1. Decreased MMP-9 expression and increased TIMP-1 expression in DN rats were significantly promoted and inhibited by deferiprone, respectively. Conclusion: Iron chelation by oral deferiprone has a renoprotective effect in DN rats by relieving oxidative stress, inflammation, and fibrosis, which is related to the cytokines NF-kappa B, MCP-1, MMP-9, TIMP-1, COX-2, and nitrotyrosine.