Upper urinary tract obstruction results in tubulointerstitial fibrosis and a progressive decline in renal function. Although several inflammatory mediators have been implicated in the pathophysiology of renal obstruction, the contribution of tumor necrosis factor- (TNF-) to obstruction-induced fibrosis and renal dysfunction has not been thoroughly evaluated. To study this, male Sprague-Dawley rats were subjected to left unilateral ureteral obstruction (UUO) vs. sham operation. Rats received either vehicle or a pegylated form of soluble TNF receptor type 1 (PEG-sTNFR1) every 84 hours. The kidneys were harvested 1, 3, or 7 days postoperatively, and tissue samples were analyzed for TNF- expression (ELISA), macrophage infiltration (ED-1 staining), TGF- 1 expression (ELISA, RT-PCR), collagen I and IV activity (Western Blot, Immunohistochemistry), -smooth muscle actin accumulation ( -SMA, Immunohistochemistry, Western blot analysis), and angiotensinogen expression (Western Blot). In a separate arm, the glomerular filtration rate (GFR; inulin clearance) of rats subjected to UUO in the presence of either vehicle or PEG-sTNFR1 was determined. Renal obstruction induced increased tissue TNF- and TGF- 1 levels, collagen I and IV activity, interstitial volume, -SMA accumulation, angiotensinogen expression and renal dysfunction, while treatment with PEG-sTNFR1 significantly reduced each of these markers of renal fibrosis. These results demonstrate that TNF- mediates obstruction-induced renal fibrosis and identify TNF- neutralization as a potential therapeutic option for the amelioration of obstruction-induced renal injury.