Prostaglandins are being commonly used to maintain the patency of the ductus arteriosus in infants with congenital ductal-dependent heart disease. A significant and unusual side effect of this drug treatment is the symmetrical development of periostitis of the long bones. A review of neonates with congenital heart disease requiring prostaglandin treatment at the Children's Hospital of Eastern Ontario revealed five infants who developed periostitis, the earliest onset being after 14 days of prostaglandin infusion. The drug dosage varied in these infants from 0.02 to 0.10 micrograms/kg/min. The periostitis was associated with limb pain and considerable swelling of the extremities in all children. The periostitis improved on cessation of the prostaglandin infusion, and by 6 weeks after the cessation of the drug, the periostitis had decreased significantly. Periostitis seemed more dependent on the duration of administration of the prostaglandin than on the dosage of prostaglandin administered. Awareness of this entity is essential not only for the treatment team caring for these infants but also for consultant pediatric orthopaedists to avoid excessive investigation for infection, metabolic disease, or vitamin deficiencies that resemble prostaglandin-induced periostitis.