We have assessed the anti-inflammatory, anti-oxidative and anti-coagulant effects of locally applied natural and recombinant hirudin in a random skin flap rat model. Thirty Wistar rats with venous congested skin flaps were randomly divided into two treatment groups and a control group to receive subcutaneous injections of natural hirudin (6 U), recombinant hirudin (6 U) or physiological saline, respectively. Superoxide dismutase, malondialdehyde and endothelin levels as well as flap survival rates of the skin flaps were measured after surgery. Compared to the control group, the treatment groups had significant higher superoxide dismutase levels and lower malondialdehyde and endothelin levels in the skin flaps. The surviving areas of the flaps were larger in the treatment groups than the control group. Our results demonstrated that hirudin could improve skin flap survival through its anti-inflammatory, anti-oxidative and anti-coagulant activities.