Abstract. Objective: In this retrospective observational study, we compared the efficacy and safety of ibuprofen lysine versus indomethacin for the medical treatment of PDA in neonates. Methods: 128 patient charts of infants born less than 32 weeks gestation with clinical or echocardiogram-confirmed diagnosis of PDA were reviewed. The success rate of ductal closure, need for additional treatment, side effects, and complications, were collected and analyzed. Results: The rate of ductal closure was similar in both groups, with 21 (32.8%) patients in the indomethacin group requiring surgical ligation and 23 (35.9%) patients in the ibuprofen group requiring surgical ligation (p = 0.17). Four patients in the ibuprofen group developed NEC requiring surgery versus one patient in the indomethacin group, however this difference was not significant (p = 0.17). Conclusions: Pharmacologic treatment of PDA with indomethacin and ibuprofen lysine yields similar results in relation to clinical efficacy. Treatment with ibuprofen lysine resulted in trend towards higher rates of surgical NEC, but was otherwise similar to treatment with indomethacin in relation to safety outcomes.