BACKGROUND Necrosis of skin flaps is considered as an important complication in reconstructive surgery. We conducted an experimental study to investigate the efficacy of low-molecular weight heparin, clopidogrel and their combination to improve the flap survival. METHODS Forty male, adult Sprague-Dawlay rats were divided randomly into 4 groups. Standard rectangular, distally based dorsal random pattern skin flap was elevated. To prevent the graft effect, a sterile sheet was put under the flap. No pharmacological agent was administered for the control group. In group 2, single subcutaneous dose of enoxaparin (3.2 mg/kg) was immediately administrated after surgery. In group 3, clopidogrel (25 mg/kg) was given orally for 7 days. In group 4, both enoxaparin and clopidogrel were administrated. The rats were evaluated on post-operative day 7 for viable and necrotic portions of flaps. RESULTS The mean and SD of necrosis was 17.79+2.5 cm in the control group, 16.20±3.1 cm in low-molecular weight heparin, 15.25+3.8 cm in combined therapy group and 13.69+2.7 cm in clopidogrel group. Clopidogrel was the only pharmaceutical agent that produced a significant increase in the flap survival area. CONCLUSION Clopidogrel may be an effective pharmaceutical agent that significantly increases viability of random skin flaps in rats, but low-molecular weight heparin and their combination did not have any significant beneficial effects.