Background: To date, a posterolateral thoracotomy approach is considered the gold standard for surgical closure of patent ductus arteriosus (PDA), also in preterm neonates. However, a posterolateral thoracotomy approach can induce post-thoracotomy lung injury of the immature and vulnerable lungs of preterm neonates. Therefore, this study aims to compare a posterolateral thoracotomy and median sternotomy for surgical closure of PDA in preterm neonates. Methods: Between September 2010 and November 2014, both surgical approaches were used to treat a symptomatic PDA in very and extremely preterm neonates. The hospital records of all these neonates were retrospectively reviewed to assess all-cause mortality and postoperative morbidity in both groups. Results: Despite comparable preoperative patient profiles, the postoperative pulmonary complication rate was significantly lower in the median sternotomy group (52.9% vs 94.7%; P = .006). Moreover, significantly lower mean airway pressures (MAPs) were seen in the median sternotomy group directly after surgery (ΔMAP median [interquartile range], 0.00 [2.13] vs 0.80 [1.67] cmH2O; P = .025). Postoperative blood transfusion (median [interquartile range], 20  vs 17  mL; P = .661) rates did not differ between both approaches. In addition, Kaplan-Meier survival analysis demonstrated no statistically significant differences between both groups. Conclusions: In our experience, a median sternotomy approach for surgical PDA closure is at least noninferior to a posterolateral thoracotomy approach. Given the lower postoperative pulmonary complication rate and lower postoperative MAPs directly after surgery, the median sternotomy approach may be considered superior for preterm neonates with immature and vulnerable lungs.