To describe our experience using acellular human dermal matrix (AlloDerm) as a full-thickness skin graft substitute for large periocular cutaneous defects. Retrospective review of the clinical records of all patients who received an acellular dermal allograft between 1997 and 2006 to reconstruct a large periocular cutaneous defect. Clinical outcomes, including graft viability, patient acceptance, and postoperative appearance, were assessed, and complications were noted. AlloDerm was used in 6 patients who were not ideal candidates for autologous skin grafts or local flap reconstruction. Four patients had severe comorbid conditions limiting the extent of surgery that could be performed safely. Four patients received AlloDerm following excision of extensive skin cancer. Two patients had extensive facial and periorbital trauma necessitating rapid defect closure at the time of primary repair. Follow-up ranged from 6 to 33 months.AlloDerm was easy to handle and shape, and it effectively covered the defects. Grafts were successfully epithelialized in all patients. One patient required a full-thickness skin graft 3 months following the original surgery for a cicatricial ectropion. No other postoperative complications were noted. Postoperative photographs demonstrated acceptable cosmetic appearance after epithelialization was complete. In patients for whom large full-thickness periorbital skin grafts or flaps are either inappropriate or extremely difficult to perform, the use of AlloDerm to cover a large cutaneous defect may be a viable option. Clinicians should consider covering large periorbital skin defects with AlloDerm in situations where autologous skin grafting or flap construction may be problematic or where extensive surgery may be hazardous to the patient.