Background: The standard treatment for persistent pulmonary hypertension of the newborn (PPHN) is inhaled nitric oxide (iNO), which is not available in Iran. Consequently, other drugs, such as milrinone, are prescribed. So far, no study has investigated the effectiveness of inhaled milrinone in the management of PPHN. The present study aimed to improve the management of PPHN in the absence of iNO. Methods: In this randomized clinical trial, neonates with PPHN, admitted to the neonatal intensive care unit of Hazrat Ali-Asghar and Akbar-Abadi hospitals, were treated with intravenous dopamine infusion and randomly divided into two groups, receiving milrinone through inhalation or infusion rout. The neonates were evaluated by Doppler echocardiography, clinical examinations, and oxygen demand test. The neonates were also evaluated for the clinical symptoms and mortality in the follow-up.Results: A total of 31 infants, with a median age of 2 days (interquartile range = 4), were included in this study. There was a significant decrease in the peak systolic and mean pulmonary arterial pressure in both inhalation and infusion groups following milrinone administration, with no significant difference between the groups (p = 0.584 and p = 0.147, respectively). There was no significant difference between the two groups regarding the mean systolic blood pressure before and after treatment. Additionally, diastolic blood pressure was significantly lower in the infusion group after treatment (p = 0.020); however, the amount of reduction was not significantly different between the groups (p = 0.928). Overall, 83.9% of the participants achieved full recovery, 75% of whom were in the infusion group and 93.3% in the inhalation group (p = 0.186).