Past studies have shown that lung angiogenic signaling may be abnormal in children with Down syndrome, but whether differences in circulating angiogenic proteins can identify pulmonary hypertension in children with Down syndrome is unknown. A prospective study of 78 children from birth to 21 years of age was conducted to evaluate clinical data, echocardiograms, and cardiac catheterizations. Four patient populations were enrolled, including children with Down syndrome who have pulmonary hypertension (Down syndrome + pulmonary hypertension, n = 12); control children without Down syndrome who have pulmonary hypertension (C + pulmonary hypertension, n = 15); children with Down syndrome without a known diagnosis of pulmonary hypertension (Down syndrome − pulmonary hypertension, n = 26); and children without Down syndrome or a known diagnosis of pulmonary hypertension (C − pulmonary hypertension, n = 25). Blood samples were collected at enrollment and concentrations for 11 proteins were evaluated. A classification tree was created to identify angiogenic peptide signals that may be associated with pulmonary hypertension in children with Down syndrome compared with controls. Findings identified elevated endostatin levels (>4.98 log10 pg/ml) were associated with Down syndrome. Platelet-derived growth factor AA levels (>2.51 log10 pg/ml) were higher in non-Down syndrome patients with pulmonary hypertension (C + pulmonary hypertension), whereas lower angiogenin (<5.428 log10 pg/ml) or lower angiogenin with elevated angiopoietin-1 levels (>3.59 log10 pg/ml) distinguished pulmonary hypertension in those with Down syndrome from the other groups. This study suggests that children with Down syndrome have high endostatin levels, but low levels of angiogenin levels in children with Down syndrome more often identified pulmonary hypertension than Down syndrome subjects without pulmonary hypertension or non-Down syndrome children. We speculate that these changes in circulating peptides support the concept of dysregulated angiogenesis in children with Down syndrome and pulmonary hypertension, which may further support potential utility as biomarkers for identifying subjects with Down syndrome at risk for pulmonary hypertension in this population.