Abstract Background: Intrauterine inflammation is associated with preterm birth and poor long-term cardiopulmonary outcomes. We aimed to determine the effect of intrauterine inflammation on the cardiopulmonary and cerebral haemodynamic transition at birth, and the response to subsequent haemodynamic challenge. Methods: Fetal instrumentation was performed at ~112 days of gestation (d: term is 147 d) for measurement of cardiopulmonary and cerebral haemodynamics. At 118 d inflammation was induced by intra-amniotic administration of lipopolysaccharide (LPS; n=7); controls (n=5) received intra-amniotic saline. At 125 d lambs were delivered and mechanically ventilated. Arterial blood gases, pulmonary and systemic arterial blood pressures and flows were measured during the perinatal period. At 10 minutes a haemodynamic challenge was administered by increasing positive end-expiratory pressure. Results. During the first 10 minutes after birth, LPS-exposed lambs had higher pulmonary vascular resistance, and lower pulmonary blood flow and left ventricular output than controls. Carotid arterial blood flow was higher in LPS-exposed lambs than controls between 3 and 7 minutes after delivery, and cerebral oxygen delivery was higher at 5 minutes. During the haemodynamic challenge, pulmonary blood flow and left ventricular output were reduced in controls but not in LPS-exposed lambs; a transient reduction in brachiocephalic arterial pressure occurred in LPS-exposed lambs but not in controls. Conclusion: Intrauterine inflammation altered the cardiopulmonary and cerebral haemodynamic transition at birth and reduced the cardiopulmonary response to a haemodynamic challenge after birth. The transient reduction in brachiocephalic arterial pressure suggests intrauterine inflammation may alter cerebrovascular control following an increase in positive end-expiratory pressure.