Background: Persistent pulmonary hypertension of the newborn (PPHN) can be primitive or a consequence of many lung diseases. We report the occurrence of PPHN after a rare disease: agenesis of the ductus venosus (ADV). Ductus venosus (DV) is a fetal vessel draining 20–30% of the oxygenated umbilical vein blood into the inferior vena cava bypassing the liver. Absent DV can be associated with a normal or abnormal umbilical vein connection to the portal vein. In the latter situation, venous umbilical blood bypasses completely the liver and drains 'unrestricted' into the inferior vena cava or into the right atrium. ADV can be associated with hydrops, chromosomal anomalies, atrial septal defects, facial clefts, kidney anomalies (1). Methods: Between 2000 and 2003, 6 cases of ADV (GA 31–37 weeks) with umbilical vein drainage into the right atrium were referred to our NICU. Results: In 4 cases PPHN, as shown by echocardiography, developed after birth; cardiomegaly was present in uterus but no hydrops. In two newborns PPHN was severe and required inhaled nitric oxide (NO); in the remaining 2 newborns mechanical ventilation and vasoactive amines were able to treat PPHN. Two newborn showed no cardiorespiratory diseases: one showed policytemia and the other mild hypoglicemia. Outcome was good in 5 newborns; in one severe encephalomalacia followed profound hypoxemia during PPHN. To our knowledge this is the first report of severe PPHN in newborns with ADV. Two main pathogenetic factors can explain this association: 1) liver bypassed by the oxygenated umbilical vein flow can result in liver hypoxia and/or in absent liver metabolism of vasoactive substances. It has been demonstrated that hypoxia enhances endothelin-1 (ET-1) gene expression in the liver (2); moreover, PPHN was found in a child with congenital porto-caval shunt suggesting a pathogenetic role of toxic metabolites reaching the pulmonary vascular bed (3); 2) in fetuses with ADV increased right cardiac output has been reported (1). Increased pulmonary blood flow can decrease NO production and increase ET-1 level in the lung as well as ET-1 receptors mediating vasoconstriction (4). Conclusion: Severe PPHN can complicate ADV. Timely and aggressive treatment of PPHN in such cases can lead to normal outcome. Understanding of the pathogenesis can help to optimise therapy.