There is no effective treatment for chronic rejection (CR) that largely limits long-term survival of kidney transplants. Transforming growth factor (TGF)-beta is a fibrogenic factor for tissue fibrosis. This study was to test the efficacy of an anti-TGF-beta antibody in preventing the CR of renal allografts in a preclinical model. Male Lewis rats (RT1(1)) were orthotopically transplanted with donor kidneys from male Fischer 344 (RT1(1v1)) rats and were treated with either anti-TGF-beta or a control antibody. The CR of renal allografts was assessed by semiquantitative histological analyses, and intragraft cytokines and fibrosis-related genes ware examined by PCR arrays. Compared with the control antibody, anti-TGF-beta antibody treatment significantly reduced recipients' proteinuria (P = 0.0002), and CR in renal transplants, which was indicated by the fewer injured renal tubules, glomeruli, and interlobular arterioles or arteries, and by less mononuclear cell infiltration and interstitial fibrosis in the anti-TGF-beta antibody-treated group (P < 0.05), but not significantly attenuate the ratios of different infiltrating leukocytes. These pathological changes were associated with downregulation of TGF-beta 1, TGF-beta 2, and proinflammatory cytokines, or with upregulation of anti-fibrotic HGF, BMP5, and BMP7. The therapeutic effect of the anti-TGF-beta antibody was further confirmed by its prevention of graft dysfunction, indicated by lower levels of serum creatinine and blood urea nitrogen or higher creatinine clearance in anti-TGF-beta antibody-treated recipients compared with those in control recipients (P < 0.05). In conclusion, the anti-TGF-beta antibody (1D11) treatment significantly reduces CR of renal allografts in rats, suggesting the therapeutic potential of this antibody therapy for treating CR of kidney transplants in patients.