Survival of random skin flap distal end depends on hemodynamic, cellular, and coagulation mechanisms. This study was designed to evaluate whether administration of ciprostene, a stable prostaglandin I2 analogue, and indomethacin, a cyclooxygenase-hydroperoxydase enzyme inhibitor, would improve the survival rate of random skin flaps. Forty-five male rats were divided into nine groups and injected with sesame oil (control), ciprostene (20 μg/kg/day), and/or indomethacin (2 mg/kg/day). Injections were done before (pretreatment for 4 days), after (posttreatment for 6 days), and before/after (pre/posttreatment for 4 and 6 days, respectively) the elevation of random dorsal skin flaps. In the pretreatment and pre/posttreatment studies, the flap survival rate of all drug-injected groups was significantly higher than that of the control group (p < 0.02). In addition, administration of ciprostene alone yielded a trend of better flap survival rate, which, however, was not statistically significant (p < 0.12). Of interest in the posttreatment study, only the simultaneous administration of ciprostene and indomethacin significantly increased skin flap viability compared with the other groups (p < 0.02). Therefore, the results demonstrated that administration of ciprostene and indomethacin either alone or together partially reversed the pathophysiological mechanisms that cause necrosis of random skin flap distal end. These pharmacological changes significantly improved random skin flap survival rate.