The introduction of neoadjuvant radiotherapy has allowed limb-preserving surgical treatment in patients with extremity soft tissue sarcoma, and the overall prognosis of this approach is similar to that of limb amputation. The benefits of this treatment, however, are often accompanied with a higher risk of major complications and blood vessel damage because of radiation-induced inflammation and necrosis of the vessel wall. In particular, it is associated with the rupture of large vessels like the femoral artery and more severe complications of wounds located in the proximal lower extremity. We present a series of four patients with soft tissue sarcoma of the thigh undergoing tumour removal and reconstruction of the defect after neoadjuvant radiotherapy. The post-operative outcome depended on the total dose of radiation used as well as the closing technique of the resulting wound. Major wound complications occurred when the irradiated skin was closed directly over the resection cavity or when local skin flaps were used. In one case, severe radiation-induced life-threatening multiple bleeding events occurred, which led to multiple flap failures. Even if the skin cover is not a problem, we propose a combined interdisciplinary approach involving immediate plastic surgical transfer of healthy, well-vascularised tissue into a defect resulting from oncological resection of sarcoma of the lower extremity following neoadjuvant radiotherapy in order to avoid secondary wound breakdown and severe bleeding complications.