Although it was once considered only a marker of glomerular damage, accumulating evidence indicates that proteinuria per se is nephrotoxic and contributes to the progression of renal injury. Several studies have demonstrated that activation of complement in proteinuric urine results in tubular and interstitial damage. It was previously demonstrated that acute complement-mediated interstitial disease is induced by C5b-9. Here the role of C5b-9 in the progression of chronic proteinuric renal disease was investigated in a nonimmunologic remnant kidney model. Five-sixths nephrectomies were performed for normocomplementemic control and C6-deficient PVG rats. Tubulointerstitial injury was assessed by measurement of two independent markers of tubular injury (i.e., vimentin and osteopontin), interstitial accumulation of the extracellular matrix components collagen type I, collagen type IV, and laminin, interstitial macrophage infiltration, and renal function. The two groups developed similar levels of proteinuria and BP. Whereas C3 deposition on the brush border was equivalent for rats in the two groups, C5b-9 deposition was observed only for normocomplementemic rats. At day 35, the degrees of both tubulointerstitial injury and renal failure were the same for the two groups. Tubulointerstitial injury in normocomplementemic rats was still severe at day 70. In contrast, interstitial injury in C6-deficient rats had improved markedly at day 70, with improvements in renal function. In a rat model of chronic progressive renal disease secondary to nephron loss, the initial interstitial changes are complement-independent and largely reversible, whereas progressive interstitial fibrosis is mediated predominantly by C5b-9. Treatment to reduce C5b-9 attack in tubular cells may slow progression and facilitate recovery.