In 24 diabetic patients with advanced renal failure (creatinine clearance [C(Cr)] < 35 mL/min), we prospectively studied serum tumor necrosis factor-alpha (TNF-alpha) levels, the possible relationship with urinary protein excretion, and the effects of pentoxifylline (PTF) administration. PTF (400 mg daily) was administered for 6 months to 14 patients, and the results were compared with data from a control group (n = 10). Baseline parameters were similar in both groups. At the end of the study, urinary protein excretion and serum TNF-alpha decreased in the active group from 2.7 (1.2 to 5.8) g/d and 569 +/- 285 pg/mL to 1.1 (0.3 to 4.0) g/d and 329 +/- 232 pg/mL, respectively (P < 0.001). By contrast, proteinuria and TNF-alpha did not change in the control group. Regression analysis showed a significant correlation between proteinuria and serum TNF-alpha both at basal (r = 0.55) and at the sixth month (r = 0.57). Furthermore, the reduction of urinary protein excretion was strongly correlated with the decrease of TNF-alpha (r = 0.72, P < 0.01). Serum Cr and C(Cr) remained stable in both groups during the study. Our findings suggest that cytokines might play a role in renal damage in diabetic nephropathy. PTF is effective in reducing proteinuria in diabetic patients with advanced renal failure. The anticytokine activity of PTF may be a further explanation for this antiproteinuric effect.