The effect of mycophenolate mofetil (MMF) and azathioprine (AZA) in reducing renal interstitial fibrosis in rats with unilateral ureteral obstruction (UUO) was studied. Fifty-nine rats with surgically induced UUO received oral MMF (n=19), AZA (n=19), or no treatment (n=21). The obstructed kidneys were analyzed by histology and morphometry on days 21 and 60 post UUO. Fibronectin- and collagen-stained areas were significantly lower in both treatment groups when compared with the control group 21 days post surgery. Transforming growth factor (TGF)-beta expression was significantly lower in the MMF-treated group than in the AZA-treated (P<0.01) and the control (P<0.001) groups. There was no significant difference in TGF-beta expression between the AZA-treated and the control groups 21 days post surgery (P>0.05). No significant difference was found in TGF-beta and fibronectin expression between treated and untreated groups on the 60th day post surgery. However, collagen expression was significantly lower in both treated groups than in the untreated group on the 60th day (P<0.005). We observed that MMF is more effective in preventing fibrosis than AZA in the UUO model in the short term; however, there is a less significant anti-fibrotic effect of these drugs in long-term than in short-term obstruction.