The aim of the present study was to investigate whether orchiectomy or administration of flutamide an antagonist of the testosterone receptor can reduce oxidative stress and histologic damage in the rat small bowel subjected to mesenteric ischemia/reperfusion (I/R) injury. A total of 32 Sprague-Dawley rats were divided into four groups. Group 1 was control (sham), group 2 was I/R, group 3 was I/R plus orchiectomy (orchiectomy was performed 14 days before I/R), group 4 was I/R plus flutamide (flutamide was given throughout 14 days before mesenteric IR). Rats were subjected to 45 min of mesenteric ischemia followed by 3 h of reperfusion. The levels of ileal malondialdehyde (MDA) and nitric oxide (NO) were found to be significantly lower in orchiectomy and flutamide treatment groups compared with I/R group (P < 0.05). The histopathological injury scores were consistent with the MDA and NO levels. These results suggest that castration or testosterone receptor blockade decreases the level of intestinal I/R injury in male rats and it is an another example for disease variations based on gender differences.