We report the development of spastic diplegia in infants during the course of interferon Alfa-2a (IFN) therapy for potentially life-endangering hemangiomas. Five infants who displayed diplegia were selected from a group of 26 infants treated with IFN. Diplegia persisted in three infants, and in the remaining two significant recovery occurred after IFN was discontinued. Magnetic resonance imaging showed no significant brain or spinal abnormalities except minor to moderate delayed myelination in two patients. Myelination was normal on subsequent radiographic examination in all five patients. We conclude that IFN can adversely affect the immature central nervous system and produce spastic diplegia, which is potentially reversible. We recommend careful clinical assessment of neurodevelopmental status during IFN therapy.