Previous studies to identify a genetic component to RDS have shown conflicting results. Our objectives were to evaluate and quantify the genetic contribution to RDS using data that comprehensively includes known environmental factors in a large sample of premature twins. Data from a retrospective chart review of twins born at < or =32 wk GA were obtained from two neonatal units. Mixed effects logistic regression (MELR) analysis was used to assess the influence of several independent covariates on RDS. A zygosity analysis, including the effects of additive genetic, common environmental and residual effects (ACE) factors, was performed to estimate the genetic contribution. Results reveal that the 332 twin pairs had a mean GA of 29.5 wk and birth weight (BW) of 1372 g. An MELR identified significant nongenetic covariates as male gender (p = 0.04), BW (p < 0.001), 5-min Apgar score (p < 0.001), and treating institution (p = 0.001) as significant predictors for RDS. The ACE model was used to estimate the genetic susceptibility to RDS by adjusting for the above factors. We found 49.7% (p = 0.04) of the variance in liability to RDS was the result of genetic factors alone. We conclude that there is a significant genetic susceptibility to RDS in preterm infants.