Importance: Hypothermia for 72 hours at 33.5 degrees C for neonatal hypoxic-ischemic encephalopathy reduces death or disability, but rates continue to be high. Objective: To determine if cooling for 120 hours or to a temperature of 32.0 degrees C reduces death or disability at age 18 months in infants with hypoxic-ischemic encephalopathy. Design, Setting, and Participants: Randomized 2 x 2 factorial clinical trial in neonates (>/=36 weeks’ gestation) with hypoxic-ischemic encephalopathy at 18 US centers in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network between October 2010 and January 2016. Interventions: A total of 364 neonates were randomly assigned to 4 hypothermia groups: 33.5 degrees C for 72 hours (n = 95), 32.0 degrees C for 72 hours (n = 90), 33.5 degrees C for 120 hours (n = 96), or 32.0 degrees C for 120 hours (n = 83). Main Outcomes and Measures: The primary outcome was death or moderate or severe disability at 18 to 22 months of age adjusted for center and level of encephalopathy. Severe disability included any of Bayley Scales of Infant Development III cognitive score less than 70, Gross Motor Function Classification System (GMFCS) level of 3 to 5, or blindness or hearing loss despite amplification. Moderate disability was defined as a cognitive score of 70 to 84 and either GMFCS level 2, active seizures, or hearing with amplification. Results: The trial was stopped for safety and futility in November 2013 after 364 of the planned 726 infants were enrolled. Among 347 infants (95%) with primary outcome data (mean age at follow-up, 20.7 [SD, 3.5] months; 42% female), death or disability occurred in 56 of 176 (31.8%) cooled for 72 hours and 54 of 171 (31.6%) cooled for 120 hours (adjusted risk ratio, 0.92 [95% CI, 0.68-1.25]; adjusted absolute risk difference, -1.0% [95% CI, -10.2% to 8.1%]) and in 59 of 185 (31.9%) cooled to 33.5 degrees C and 51 of 162 (31.5%) cooled to 32.0 degrees C (adjusted risk ratio, 0.92 [95% CI, 0.68-1.26]; adjusted absolute risk difference, -3.1% [95% CI, -12.3% to 6.1%]). A significant interaction between longer and deeper cooling was observed (P = .048), with primary outcome rates of 29.3% at 33.5 degrees C for 72 hours, 34.5% at 32.0 degrees C for 72 hours, 34.4% at 33.5 degrees C for 120 hours, and 28.2% at 32.0 degrees C for 120 hours. Conclusions and Relevance: Among term neonates with moderate or severe hypoxic-ischemic encephalopathy, cooling for longer than 72 hours, cooling to lower than 33.5 degrees C, or both did not reduce death or moderate or severe disability at 18 months of age. However, the trial may be underpowered, and an interaction was found between longer and deeper cooling. These results support the current regimen of cooling for 72 hours at 33.5 degrees C. Trial Registration: clinicaltrials.gov Identifier: NCT01192776.