<i>Background:</i> Chronic twin-to-twin transfusion syndrome (TTTS) is a complication of monochorionic twin gestations and is associated with high perinatal mortality and increased neurological, cardiovascular and renal morbidity. <i>Objective:</i> To report the risk of severe persistent pulmonary hypertension of the newborn (PPHN) in TTTS and discuss the possible association between severe PPHN and TTTS. <i>Methods:</i> All cases of monochorionic twins with severe PPHN at birth admitted to our nursery between June 2002 and July 2006 were reviewed retrospectively. We compared the incidence of severe PPHN in monochorionic twins with and without TTTS. Severe PPHN was diagnosed according to clinical and ultrasound criteria when an infant with a structurally normal heart had (1) severe hypoxemia and (2) evidence of a right-to-left shunt on persistent ductus arteriosus or foramen ovale, requiring treatment with inhaled nitric oxide (iNO). <i>Results:</i> In a consecutive series of 73 twin pregnancies with TTTS, 4 of the 135 live-born twins (3%) were affected by severe PPHN. All reacted promptly to treatment with iNO. The incidence of severe PPHN in monochorionic twins without TTTS was 0% (0/161). <i>Conclusion:</i> In view of the severe clinical course in PPHN and need for adequate and prompt treatment with iNO, perinatologists should be aware of the increased risk of severe PPHN in TTTS.