Preterm male infants are at a disadvantage when compared with female infants regarding the incidence of respiratory and neurologic morbidity and mortality. At term, female infants from unlike-sex twin pairs have birth weights that are closer to their male co-twins than to girls from like-sex twin pairs. We hypothesized that if the male disadvantage is mediated via factors that affect fetal lung development, there may be a potential effect on the incidence of respiratory distress syndrome and its complications in female infants from unlike-sex pairs. In this population-based study we used data from the Israel Neonatal Network, which included data from 8858 very low birth weight (500-1500 g) infants of 24 to 34 weeks' gestation. The incidence of morbidity and mortality was compared in male and female infants from singletons and like-sex and unlike-sex twin pairs. Multivariable analyses were used, accounting for relevant confounding variables. Male singletons and like-sex twins were at increased risk for mortality, respiratory distress syndrome, pneumothorax, bronchopulmonary dysplasia, periventricular-intraventricular hemorrhage, and periventricular leukomalacia. However, in unlike-sex twin pairs, no difference was seen in the incidence of respiratory morbidity between male and female twins. The male disadvantage was maintained for mortality and periventricular-intraventricular hemorrhage. These findings suggest that the difference in morbidity and mortality between male and female premature infants represents a male disadvantage as opposed to a female advantage and that this disadvantage may be transferred from boys to girls in unlike-sex twin pairs, perhaps via an intrauterine paracrine effect.