Background <p>Neonates with persistent pulmonary hypertension (PPHN) are a circulatory transition disorder characterized by a persistent increase in pulmonary vascular resistance. Unfortunately, there are several neonatal intensive care units (NICUs) where echocardiography may not always be easily accessible, particularly in middle- and low-income countries. Thus, the need for a rapid and potentially reliable biomarker for the early diagnosis of PPHN is necessary. So, in this study, we aimed to elucidate the role of pentraxin-3 (PTX-3) as an early diagnostic biomarker for neonatal persistent pulmonary hypertension.</p> Methods <p>This prospective case-control study included 50 neonates with PPHN in parallel with 50 age and sex-matched neonates as a control group. All newborns were admitted to the NICU of Menoufia University Hospital. Serum level of PTX-3 was evaluated using a commercial sandwich enzyme-linked immunosorbent test (ELISA) kit.</p> Results <p>Neonates with PPHN had a significantly increased level of PTX-3 compared to neonates in the control group (<i>p</i> = 0.008). At a cut-off value of 1448.5 pg/ml, serum PTX-3 showed a 92% sensitivity and 76% specificity for diagnosing PPHN. PTX-3 levels were positively correlated with estimated Pulmonary Artery Systolic Pressure (ePASP) (<i>r</i> = 0.297, <i>p</i> = 0.003).</p> Conclusion <p>Neonates with persistent pulmonary hypertension had a higher serum PTX-3 level, making it a potential indicator for predicting PPHN. To confirm our findings and clarify the role of serum PTX-3 in a range of neonatal disorders, more research is necessary.</p>