The Preterm Epo Neuroprotection (PENUT) Trial randomized 936 infants 24-0/7 to 27-6/7 weeks’ gestation to high dose Epo or placebo in the first 24 hours after birth. Infants received either 1000 IU/kg IV every other day for 6 doses or placebo, followed by 400 IU/kg/day SQ or sham injections on MWF through 32 completed weeks post menstrual age (PMA). The primary outcome was defined as death or severe neurodevelopmental impairment (NDI): cerebral palsy or Bayley-III Motor or Cognitive Scores < 70) at 22-26 months PMA. Subjects underwent a head ultrasound and blood sampling on day 1 prior to study drug dosing. Epo, interferon γ, TNF α, IL 6, 8, and 10 were assayed by Meso Scale Discovery. Data were analyzed using Generalized Estimating Equations (GEE) with robust standard errors to account for twins/multiples, adjusting for treatment assignment and age at birth. A multivariable GEE model was used to evaluate the independent contribution of biomarkers found to be associated with the primary outcome. Baseline factors (present in 1st 24 hours of age) associated with death or NDI included low gestational age, any day 1 intracranial hemorrhage, (p<0.001), elevated baseline Epo and IL-10 levels (p=0.034 and 0.031, respectively), Hispanic ethnicity (p=0.017) and low Apgar score (p<0.001). Late predictors included multiple transfusions, pulmonary hypertension (p<0.001), pneumothorax (p=0.02), intubated > 1 week (0.01), BPD at 28 days (p<0.001) white matter injury (p<0.0001), ROP surgery performed (p=0.02) and hydrocephalus (p<0.0001). Trial registration number: NCT01378273.