Renal tubulointerstitial fibrosis (TIF) is the common end stage of various chronic renal diseases, and pirfenidone (PFD) is a novel, broad-spectrum anti-fibrotic compound but little is known about its effect and mechanism of action on renal TIF. In this work, we employed a unilateral ureteral obstruction (UUO) rat model to investigate the apoptosis of renal tubular epithelial cells (RTC) after PFD treatment. Thirty-five Sprague Dawley (SD) rats were randomized into three groups: sham-operated group (=7), UUO group (=14) and PFD group (=14). All rats were sacrificed at day 7 or 14 after operation. Renal histology was studied by using periodic acid schiff reagent (PAS) and Masson trichromic stain (MASSON); apoptosis was detected by terminal deoxynucleotide transferase-mediated dUTP-biotin nick end-labeling (TUNEL); tubular caspase-3 expression was assessed by immunohistochemistry. The content of malondialdehyde (MDA) and total activity of superoxide dismutase (T-SOD) in the renal cortex was determined by chemical colorimetry method. TIF, apoptosis of RTC, tubular expression of caspase-3 and the content of MDA were increased in the UUO group compared with those in the sham-operated group, and were ameliorated significantly by PFD treatment (<0.05). The activity of SOD was decreased in the UUO group, but was improved by PFD treatment (<0.05). Our results showed that PFD could ameliorate TIF in the UUO group, and the possible mechanism was by reducing the apoptosis of RTC, which involved oxidative stress and caspase-3.