Down syndrome (DS) patients have an increased risk of developing pulmonary hypertension later in life compared to age-matched controls. The goal of this study was to determine if the incidence of persistent pulmonary hypertension of the newborn (PPHN) is also higher in neonatal DS patients compared to the general population. A retrospective chart review of DS patients admitted during a 3-year period to the neonatal intensive care unit was performed. DS patients with meconium aspiration syndrome, pulmonary infections, or pulmonary space-occupying lesions were excluded. DS patients were divided into four groups based on treatment and consisted of no intervention (A), supplemental oxygen (B,) mechanical ventilation use (C), and inhaled nitric oxide administration (D). Group D was defined as having PPHN. z test of the difference between sample and known population, chi-square, t-test, and analysis of variance with Tukey adjusted post hoc test were used for analysis. p < 0.05 was considered significant. A total of 58 patients met inclusion criteria. Twenty-four DS patients were in group A, 17 in group B, 10 in group C, and 7 in group D. There was no difference between the four groups for gender (males: 10, 5, 5, and 5, respectively), gestational age (36.4, 38.2, 36.4, and 36.4 weeks, respectively), weight (2.8, 3.0, 2.4, and 3.0 kg, respectively), or the presence of congenital heart defects (17, 10, 6, and 1, respectively). The estimated number of DS patients born in the state of Ohio during this period was 598; therefore, the incidence of PPHN in DS was 1.2%. The reported incidence of PPHN is 0.1%. The Reported incidence of PPHN was significantly lower versus the incidence of PPHN in DS (z = 2.7, p = 0.007). It was concluded that DS patients have an increased incidence of PPHN compared to historical controls regardless of baseline demographics.