Prostaglandin E1 (PGE1) is the drug of choice for providing ductal patency in cyanotic congenital heart disease (CCHD) for a short period of time until essential surgical management. Occasionally, prolonged use of PGE1 is required when the surgical procedure is delayed due to certain clinical conditions. Prolonged use of PGE1 may lead to bone and tissue changes such as pretibial and soft tissue swelling of the extremities and reversible cortical proliferation of the bones. Venous stasis as an additional risk factor can result in generalized periosteal reaction that initially can cause the separation of the periosteum from the cortex. We report an infant with CCHD who developed severe tissue swelling and generalized periosteal reaction due to coexistence of prolonged use of PGE1 and venous stasis. To the best of our knowledge, this is the first case report with both of these risk factors.