BACKGROUND Epidermolysis bullosa (EB) is a group of rare genetic conditions that can cause eruption of blisters on the skin and mucous membranes by the slightest mechanical stimulus. In these patients particular attention should be paid to potential complications, from monitoring of vital signs to anesthesia procedures in the perioperative period. CASE REPORT A 31-year-old man with EB underwent lower-leg amputation for squamous cell carcinoma. Multiple blisters and scars had appeared all over his face and body, and his extremities were contracted. The patient's mouth could open only up to approximately 5 mm, and laboratory examination showed a high inflammatory response. In addition, he had anemia and hypoalbuminemia with a serum albumin concentration of 1.4 g/dL. We planned sciatic and femoral nerve blocks with sedation for anesthesia management because of the anticipated difficulty of intubation and concern about postoperative upper-airway obstruction due to changes in the oral cavity. While protecting the skin from external force application, we performed sciatic and femoral nerve blocks (1.7 mg/kg) using 0.25% levobupivacaine, 10 mL (3.5 mg/kg) of 1% mepivacaine, and 6.6 mg of dexamethasone. Good analgesia was achieved, and the patient was stable during the operation. The patient was discharged 12 days postoperatively without additional signs of infection or new blister formation, although surgical wound healing was delayed. CONCLUSIONS For patients with EB who have had repeated blistering and scarring, even from a minor external force, attention should be paid to airway management and avoidance of additional skin damage caused by external forces.