Pulmonary vascular disease (PVD) represents an underestimated and increasing clinical burden not only in the neonatal period but also later in life, when exercise tolerance is decreased. Animal models performing long-term followup after a perinatal insult are lacking. This study aimed to develop and characterize a neonatal swine model with hypoxia-induced PVD during long-term followup after reexposure to normoxia and to investigate the exercise response in this model. Piglets were exposed to a normoxic ( n = 10) or hypoxic environment ( n = 9) for 4 wk. Neonatal hypoxia exposure resulted in pulmonary hypertension. Mean pulmonary artery pressure was elevated 1 day after reexposure to normoxia (30.2 ± 3.3 vs. 14.3 ± 0.9 mmHg) and remained significantly higher in the second week (32.8 ± 3.8 vs. 21.4 ± 1.2 mmHg), accompanied by decreased exercise tolerance. Exercise resulted in a trend toward an exaggerated increase of pulmonary artery pressure in hypoxia-exposed animals ( week 6, P = 0.086). Although pulmonary hypertension was transient, thickening of pulmonary arterioles was found at the end of followup. Furthermore, right ventricular dilation, lower right ventricular fractional area change ( week 8, 40.0 ± 2.7% vs. 29.5 ± 4.7%), and tricuspid annular plane systolic excursion ( week 8, 27.0 ± 2.5 vs. 22.9 ± 2.1 mm) persisted during followup. Male animals showed more severe PVD than female animals. In conclusion, we developed a neonatal swine model that allows examination of the long-term sequelae of damage to the developing neonatal lung, the course of the disease and the effect of therapy on long-term outcome. NEW & NOTEWORTHY The swine model of neonatal pulmonary vascular disease developed in the present study is the first that allows exercise testing and examination of long-term sequelae of a perinatal hypoxic insult, the course of the disease, and the effect of therapy on long-term outcome.