This patient series reports on prolonged hyperinsulinism in four newborn infants without characteristic perinatal risk factors. The condition presented with asymptomatic hypoglycemia soon after birth and was accompanied by inappropriately elevated plasma insulin levels and suppressed ketogenesis and lipolysis. Glucose infusion rates between 11 and 20 mg/kg/min were necessary for correction of hypoglycemia. Sustained euglycemia could be achieved only after starting diazoxide. In all infants, diazoxide could be weaned off within weeks without the recurrence of hypoglycemia. This case series illustrates the varied perinatal history and clinical course of prolonged neonatal-onset hyperinsulinism and highlights the importance of considering this condition in infants without typical predisposing factors.