In the present study we investigated whether donor gender or the effects of sex hormones play the greater role in the development of chronic allograft nephropathy. Kidneys of male and female Fisher rats were orthotopically transplanted into castrated male Lewis recipients. Animals were treated with testosterone, estradiol, or vehicle and the kidneys were harvested 20 weeks after transplantation for histological, immunohistological, and molecular analysis. Testosterone treatment resulted in increased proteinuria and profound glomerulosclerosis, irrespective of donor gender. In addition, mRNA levels of transforming growth factor-beta1 (TGF-beta1) and platelet-derived growth factor-A and B (PDGF-A and B) chains were enhanced in these allografts. Estradiol reduced glomerulosclerosis and mononuclear cell infiltration in allografts of both genders that paralleled a decreased mRNA expression of TGF-beta1, PDGF-A and B. No donor gender-related differences were noted in vehicle-treated animals. Our findings demonstrate that sex hormones rather than donor gender have a significant impact on chronic allograft nephropathy.