Xeroderma pigmentosum (XP) is characterized by photohypersensitivity of sun-exposed tissues and several thousand-fold increased risk of developing malignant neoplasms of the skin and eyes. Inherited molecular defects in nucleotide excision repair genes cause the autosomal recessive condition XP. A 56-year-old woman with XP presented with an extensive multirecurrence basal cell carcinoma in the left naso-orbital region. At the time of the first visit, the patient had already received several interventions with local reconstructive techniques, a full course of radiotherapy, and bilateral neck dissection. A large tumor resection and free flap reconstruction were performed. Three years 9 months afterward, an aggressive recurrence occurred, and a second resection was needed. A new free flap was transferred, and microvascular anastomoses were done to the pedicle of the previously transferred flap. Nine months later, the patient returned with frontal bone tumoral lesions, and third microsurgical intervention was done. At that time, the reconstruction was practiced by a composite chimeric flap with a rib portion. Its pedicle was anastomosed to the one of the second free flaps. The objective of this article was to report the authors’ experience concerning a unique case of XP requiring a complex reconstruction of the anterior skull base. Xeroderma pigmentosum patients need an early diagnosis and removal of cutaneous tumor lesions as some of them behave aggressively, especially those affecting the face. Free flaps are good solutions for reconstruction and should proceed from non–sun-exposed areas of the body. If reconstructed areas are highly radiated and/or skin tumors affect deep anatomical areas, complications are frequent.