© 2020 American Medical Association. All rights reserved. Importance: The Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network (NRN) extremely preterm birth outcome model is widely used for prognostication by practitioners caring for families expecting extremely preterm birth. The model provides information on mean outcomes from 1998 to 2003 and does not account for substantial variation in outcomes among US hospitals. Objective: To update and validate the NRN extremely preterm birth outcome model for most extremely preterm infants in the United States. Design, Setting, and Participants: This prognostic study included 3 observational cohorts from January 1, 2006, to December 31, 2016, at 19 US centers in the NRN (derivation cohort) and 637 US centers in Vermont Oxford Network (VON) (validation cohorts). Actively treated infants born at 22 weeks' 0 days' to 25 weeks' 6 days' gestation and weighing 401 to 1000 g, including 4176 in the NRN for 2006 to 2012, 45179 in VON for 2006 to 2012, and 25969 in VON for 2013 to 2016, were studied. VON cohorts comprised more than 85% of eligible US births. Data analysis was performed from May 1, 2017, to March 31, 2019. Exposures: Predictive variables used in the original model, including infant sex, birth weight, plurality, gestational age at birth, and exposure to antenatal corticosteroids. Main Outcomes and Measures: The main outcome was death before discharge. Secondary outcomes included neurodevelopmental impairment at 18 to 26 months' corrected age and measures of hospital resource use (days of hospitalization and ventilator use). Results: Among 4176 actively treated infants in the NRN cohort (48% female; mean [SD] gestational age, 24.2 [0.8] weeks), survival was 63% vs 62% among 3702 infants in the era of the original model (47% female; mean [SD] gestational age, 24.2 [0.8] weeks). In the concurrent (2006-2012) VON cohort, survival was 66% among 45179 actively treated infants (47% female; mean [SD] gestational age, 24.1 [0.8] weeks) and 70% among 25969 infants from 2013 to 2016 (48% female; mean [SD] gestational age, 24.1 [0.8] weeks). Model C statistics were 0.74 in the 2006-2012 validation cohort and 0.73 in the 2013-2016 validation cohort. With the use of decision curve analysis to compare the model with a gestational age-only approach to prognostication, the updated model showed a predictive advantage. The birth hospital contributed equally as much to prediction of survival as gestational age (20%) but less than the other factors combined (60%). Conclusions and Relevance: An updated model using well-known factors to predict survival for extremely preterm infants performed moderately well when applied to large US cohorts. Because survival rates change over time, the model requires periodic updating. The hospital of birth contributed substantially to outcome prediction.