Patent ductus arteriosus (PDA) is a frequent complication in preterm infants. Ibuprofen and indomethacin (both COX inhibitors) are used for pharmacological closure of PDA. In most centers, a failed second course of COX inhibitors is followed by surgical closure. Our aim was to estimate the closure rate of clinically significant PDA after second and third courses of ibuprofen and record possible side effects. A study population, consisting of 164 preterm infants (<32 weeks' gestational age) with PDA admitted at our tertiary care center between November 2005 and September 2011, was retrospectively analyzed. Primary outcome was the closure rate after repeated courses of ibuprofen. The closure rate was similar after the first (109/164), second (24/43), and third (6/11) course of ibuprofen (X (2) = 2.1, p = 0.350). Late start of the first course of ibuprofen was a predictive factor for increased need of a second course (X (2) = 4.4, p = 0.036). No additional side effects of multiple courses of ibuprofen were detected. In conclusion, repeated courses of ibuprofen are an effective and safe alternative for surgical closure and should be considered after failure of the first course of ibuprofen.