Background: Persistent pulmonary hypertension of the newborn (PPHN) is a critical problem facing neonatologists and pediatric cardiologists. Aim of the work: To outline the incidence of PPHN, the different etiologies underlying the disease and the efficacy of some modalities used for treatment including Milrinone. Patients and methods: This is a prospective descriptive study. All neonates admitted to the outborn tertiary level neonatal intensive care unit of Cairo University Pediatric Hospital during the period from the beginning of October 2010 till the end of March 2011 were subjected to echocardiographic estimation of their systolic pulmonary artery pressure (SPAP). Accordingly, they were classified into 3 groups; Group A (SPAP < 30 mmHg), Group B (SPAP 30-49 mmHg), and Group C (SPAP ≥ 50 mmHg). Results: 225 neonates were enrolled in our study. 85 neonates (37.8%) were diagnosed by echocardiography to have PPHN (SPAP ≥ 30 mmHg). PPHN was more common in males (59 males vs. 26 females). It was also more common in neonates delivered by cesarean section (59 (69.4%) vs. 26 (30.6%) delivered vaginally). Respiratory distress syndrome (RDS) was the most common underlying diagnosis of pulmonary hypertension in our unit. There was statistically significant improvement of the oxygen saturation (P=0.000), capillary blood gases, and SPAP (P=0.000) after completion of conventional therapy in Group B. Milrinone was given to Group C in addition to conventional therapy. All of the previous monitoring parameters showed statistical improvement after treatment with Milrinone. Neonates who received Milrinone did not become hypotensive and there was a significant drop in heart rate (P=0.000) after 24 hours of starting treatment. The mortality rate among neonates with pulmonary hypertension was 36/85 neonates (42.3%). Conclusion: Conventional therapy is effective in the management of neonates with mild-to-moderate PPHN. Intravenous Milrinone as an adjuvant to conventional therapy is effective when used in neonates with moderate-to-severe PPHN. It reduces pulmonary artery pressure and improves oxygenation without compromising systemic blood pressure.