The beneficial effects of pentoxifylline (PTX), which has an anti-inflammatory and renoprotective effect in diabetic nephropathy, are not completely understood. This study investigates whether prolonged administration of PTX (40 mg/kg, per oral) is effective in streptozotocin-induced diabetic nephropathy. The amount of urinary protein was higher in the diabetic rats than in the control rats. The amount remained unchanged after 4 weeks and decreased after 8 weeks of PTX treatment. Accumulation of monocyte chemoattractant peptide-1 (MCP-1) and mouse monoclonal anti-monocyte/macrophage antibody (ED-1) positive cells was higher in untreated diabetic rats than in the control rats. PTX administration ameliorated the urinary MCP-1 excretion and interstitial infiltration of ED-1 positive cells at 4 weeks. Further, in diabetic rats, administration of PTX for 4 weeks inhibited the renal inflammatory reaction, and when administration for 8 weeks, it prevented proteinuria. These findings support the hypothesis that prolonged administration enhances the protective effects of PTX.