Rationale: Persistent pulmonary hypertension of the newborn ( PPHN) is a syndrome of failed circulatory adaptation at birth with persisting increased pulmonary vascular resistance that is associated with high mortality rates especially in preterm infants. Patient concerns: We reported 2 cases of PPHN in preterm infants with respiratory distress syndrome and early onset sepsis refractory to therapy with vasopressors, inotropes, and inhaled nitric oxide (iNO), in whom treatment with treprostinil was successful. Diagnoses: Infants showed a difference of more than 10% between pre- and postductal saturation of peripheral oxygen by pulse oximetry. Echocardiogram showed flattened ventricular septum, right to left shunting through the patent ductus arteriosus, and tricuspid regurgitation velocity above 2.9 m/s. Interventions: The patients received treprostinil through central venous line because iNO therapy was not effective. Outcomes: Within 6 to 12hours after treatment with treprostinil, the patients showed dramatic clinical improvement, and no systemic side effects were observed, including intraventricular hemorrhage (≥grade II). Lessons: IV treprostinil might be given to preterm infants with severe PPHN, who did not respond to conservative therapies, including iNO.