Oral ibuprofen is being used as an alternative to indomethacin in medical management of patent ductus arteriosus (PDA), but limited data exist on oral efficacy of these drugs for PDA closure in India. To assess and compare the efficacy of oral ibuprofen and oral indomethacin for PDA closure in preterm Indian neonates, we designed a randomized controlled study on clinically diagnosed and echocardiographically confirmed hemodynamically significant PDA in preterm neonates. Patients were assigned to receive either oral ibuprofen at a dosage of 10, 5, 5 mg/kg every 24 h or three doses of oral indomethacin (0.20-0.25 mg/kg every 24 h) starting on the third day of life or when diagnosed. A second course of ibuprofen/indomethacin was given, if PDA failed to close within 48 h after the first course. Patients were monitored for complications like oliguria, bleeding, necrotizing enterocolitis, intraventricular hemorrhage, oxygen dependency, and gastrointestinal side effects. The baseline characteristics were comparable in both groups. Of the 83 children enrolled, 57.8 % received oral ibuprofen and 42.1 % received oral indomethacin. The overall closure rate of PDA was 60 and 65.7 % in the ibuprofen and indomethacin groups, respectively. Closure rate was significantly higher when the drugs were administered at an early postnatal age (<8 days) (83.3 % [p = 0.02] in the indomethacin group and 75 % [p = 0.03] in the ibuprofen group) in neonates >28 weeks (ibuprofen group 66.7 % [p = 0.02]; indomethacin group 65.5 % [p = 0.04]) and in babies with birth weight >1,000 g (ibuprofen group 62.2 %; indomethacin group 70 % [p = 0.04 in both groups]). Complications were similar in both groups. The efficacy of both drugs was similar. Poor closure in our study could be because of genetic differences in pharmacokinetics of drug metabolism in the Indian population. Regimens with higher doses or increased duration of treatment may increase the frequency of closure. Studies with larger numbers of subjects with evaluation of pharmacokinetic parameters are therefore required.