Familial incontinentia pigmenti (IP) (OMIM #308300) is a rare genetic disorder which segregates in an X-linked dominant way. The female-to-male ratio ranges from 20 to 37 : 1. In affected females IP causes highly variable abnormalities of the skin, hair, nails, teeth, eyes, and central nervous system (CNS). Cardiovascular anomalies, cerebral infarction, and immune dysfunction are rare complications of IP. The pathogenesis of cerebral changes in IP remains elusive. We report the case of two IP-affected sisters who presented in each case with neonatal seizures on the fifth day of life. Via cranial magnetic resonance tomographic imaging (MRI) different types of lesions in both hemispheres were demonstrable in both patients. To date the pathogenetic mechanisms for the cerebral lesions are not fully understood. However, multiple microscopic infarcts could serve as a possible explanation. The clinical course and the neurological development of the older child are favorable and so far the younger sibling appears to be developing normally, which is uncommon for patients with early onset of neurological symptoms. Symptomatic seizures in IP are an important differential diagnosis in benign non-familial and familial neonatal seizures.