BACKGROUND Patent ductus arteriosus (PDA) is a common disease in premature neonates, which could occur in up to 50% of the neonates weighting <1000 g. PDA might induce hemodynamic and respiratory disorders and increase mortality and morbidity. This study aimed to compare the effectiveness of oral ibuprofen and a low dose of intravenous acetaminophen in the management of PDA. METHODS This randomized double-blind clinical trial was conducted on the preterm neonates with an equal gestational age of <34 weeks and weight of >1000 g with symptomatic PDA, who were admitted in Shahid Beheshti and Al-Zahra Hospitals Affiliated to Isfahan University of Medical Sciences, Iran. In total, 40 preterm neonates were examined, 20 of whom received 15 mg/kg/6 h of intravenous acetaminophen for 2 days and 20 infants received 10 mg/kg of intravenous ibuprofen on the 1st day and 5 mg/kg for the next 2 days, and the results include vital signs and echocardiography findings were compared. RESULTS In the acetaminophen and ibuprofen groups, 16 (80%) and 17 neonates (85%) responded (PDA closure rate) to the treatment, respectively (P = 0.68). Furthermore, acetaminophen and ibuprofen have a similar effect on vital signs. Both drugs did not change in blood pressure, but they reduced the respiratory rate and heart rate after treatment. CONCLUSIONS Low-dose acetaminophen compared to ibuprofen has an equal effectiveness in the closure of PDA.