Abstract. Objectives: To determine the safety, efﬁcacy, and cost of a second course of oral ibuprofen (OI) in closure of patent ductus arteriosus (PDA) in preterm infants. Material and methods: Preterm infants ≤34 weeks gestational age (GA) who had clinically signiﬁcant PDA at a postnatal age from 48–120 hours were subjected to initial oral ibuprofen course and evaluated by echocardiography. Failure of PDA closure was followed by a second course of three doses of OI. Results of echocardiography and laboratory investigations were compared before and after each ibuprofen course. The cost of ibuprofen was calculated for each patient. Results: One-hundred patients were enrolled; their mean gestational age was 31.3 ± 1.3 weeks and mean birth weight was 1350 ± 271 g. A total of 76 infants (76%) had PDA closed after the ﬁrst course and an additional 9/19 patients (47.5%) had PDA closure after the second course. Respiratory improvement and signiﬁcant decrease in the fraction of inspired oxygen were observed (P < 0.001 and P = 0.02, respectively). Nonsigniﬁcant changes regarding urine output, renal function and platelet count were encountered after the second course. Among the 19 infants who received two courses of ibuprofen, only one (5%) had intraventricular hemorrhage. The cost of oral ibuprofen dosage was trivial ($0.20). Conclusion: Oral ibuprofen is an inexpensive drug that can be used effectively for PDA closure in premature infants. A second course of ibuprofen further improves the efﬁcacy of the drug without clear short-term complications. Large scale trials are needed to examine side effects and long term sequelae.