Key PointsQuestionCan circulating biomarkers improve estimations of neurodevelopmental outcomes at 2 years compared with clinical information alone?FindingsIn this secondary analysis of a randomized clinical trial of 180 neonates with hypoxic ischemic encephalopathy and complete biomarker and outcome data, erythropoietin treatment did not affect the measured circulating biomarker concentrations. A combination of inflammatory mediators and brain-specific proteins drawn at baseline, day 2, and day 4 significantly improved accuracy for estimation of neurodevelopmental outcomes vs that obtained with clinical data alone.MeaningThese findings suggest that circulating biomarkers may improve projection of 2-year outcomes for newborns with hypoxic ischemic encephalopathy.