Spina bifida is the most common birth defect of the CNS, with meningomyelocele observed in 1 in 800 to 1000 infants. A single reliable method of providing adequate soft-tissue coverage (skin, but also including subcutaneous fat, fascia, and muscle) of the meningomyelocele defect while preventing dehiscence and infection has yet to be defined. This study reviews a case series of 3 patients with large meningomyeloceles treated by a single neurosurgeon /plastic surgeon team at a single institution. Following repair of the neural elements (both dura and neural placode), soft-tissue coverage (skin, but also subcutaneous tissue and fascia) was achieved using acellular dermal matrix over the neural elements, repaired with sutures, and covered with skin flaps. In this series of 3 patients, stable coverage was achieved in all patients. One patient experienced minor wound dehiscence treated with debridement and primary closure with simple relaxing incisions. This series demonstrates that the usage of acellular dermal matrix provides a stable soft-tissue coverage for large meningomyelocele defects in an easily reproducible operation preserving local soft tissue (muscle, fascia) for potential salvage operations or revisions (such as for scoliosis) as well as providing a less demanding operation on the fragile physiology of the neonate.