Although blockade of renin-angiotensin system have been cited as the first line of therapy for the management of diabetic nephropathy (DN), however in a substantial number of patients, progression of renal disease are not completely halted by these agents. We have conducted a double blinded clinical trial to assess the additive effect of pentoxifylline on reduction of proteinuria among patients with type 2 DM under blockade of angiotensin system. The dosage of PTX used in our trial was at a low dosage of 400mg daily and to our knowledge, we did not found article which evaluated the antiproteinuric effect of pentoxifylline in this dosage. One hundred patients with DN and persistent proteinuria despite treatment with losartan and enalapril in at least 3 months before inclusion in the study were randomly assigned to two groups. Control group (n=50, 26 males and 24 females) received losartan and enalapril, while treatment group (PTX Group) (n=50, 28 males and 22 females) was given losartan, enalapril and pentoxifylline 400mg/day for 6 months. At the beginning of the study there were no significant differences in demographic and clinical characteristics of patients including serum creatinine, HbA1c, blood pressure and urinary protein excretion between two groups (P>.05). In the PTX group, the mean rate of urinary protein excretion have significantly decreased from 616.66mg to 378.24 after 3 months (P=.000) and to 192.05mg after 6 months (P=.000) whereas no significant changes were observed in the control group. The beneficial antiproteinuric effect of PTX was not associated to the degree of metabolic control and a reduction of blood pressure. In addition, at the end of study, the mean clearance of creatinine was significantly higher in PTX group (P=.04). In conclusion, PTX can significantly provide additive antiproteinuric effect and slow the decrease in GFR among patients with type 2 DM under blockade of angiotensin system.