ImportanceTherapeutic hypothermia (TH) is the standard of care to improve outcomes following neonatal hypoxic-ischemic encephalopathy (HIE), but mortality and morbidity remain high, prompting research into treatment adjuncts.ObjectiveTo assess whether erythropoietin (EPO) plus TH improves outcomes in infants with moderate or severe HIE.Design, setting, and participantsThe PAEAN (Preventing Adverse Outcomes of Neonatal Hypoxic Ischaemic Encephalopathy with Erythropoietin) study was a phase 3, multicenter, double-blinded, placebo-controlled randomized clinical trial conducted in 24 neonatal intensive care units in Australia, New Zealand, and Singapore. Infants 35 weeks' gestation or older, less than 23 hours old, with perinatal depression (umbilical cord arterial pH <7.0 or base excess ≥12 mmol/L or, at 10 minutes, Apgar score ≤5 or still receiving resuscitation), and moderate or severe HIE (modified Sarnat criteria) who had commenced TH within 6 hours of birth were eligible for inclusion. Study recruitment was conducted between May 2016 and March 2021, with data collection completed in September 2024. Data analysis was performed from September 2024 to October 2025.InterventionIntravenous EPO, 1000 IU/kg (5 doses over the first week), or placebo.Main outcomes and measuresThe primary outcome was a composite of death or moderate or severe motor or cognitive disability using standardized neurological and developmental assessments at 2 years. Moderate or severe disability comprised motor deficit (diagnosis of cerebral palsy with Gross Motor Function Classification Scale score ≥2) or moderate or severe cognitive deficit using Bayley Scales of Infant Development, Third Edition. Secondary outcomes included death, disabilities alone, and safety.ResultsFrom 2016 to 2021, 313 infants were randomized (EPO: n = 156; placebo: n = 157). Baseline characteristics (including mean [SD] gestational age at birth: 39.4 [1.7] weeks vs 39.3 [1.6] weeks and ratio of moderate:severe encephalopathy: 78%:22% vs 77%:23%) and loss to follow-up (10.2% overall) were similar across both groups. There were 67 (42.9%) and 59 (37.6%) female infants, respectively. There was no significant difference in the primary outcome (EPO: 47 of 138 [34.1%] vs placebo: 41 of 143 [28.7%]; relative risk, 1.19; 95% CI, 0.84-1.68; P = .33), in secondary outcomes (death: 22 of 146 [15.1%] vs 18 of 149 [12.1%]; P = .45; cerebral palsy: 22 of 120 [18.3%] vs 22 of 127 [17.3%]; motor deficit: 13 of 120 [10.8%] vs 15 of 127 [11.8%]; cognitive deficit: 20 of 113 [17.7%] vs 16 of 118 [13.6%]), or in any safety outcomes.Conclusions and relevancePer the results of this multicenter randomized clinical trial, EPO did not demonstrate any adjunctive effect to hypothermia, but no safety concerns were evident.Trial registrationanzctr.org.au Identifier: ACTRN12614000669695.