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Abstract This study used machine learning and a national prospective cohort registry database to analyze the major risk factors of necrotizing enterocolitis (NEC) in very low birth weight (VLBW) infants, including environmental factors. The data consisted of 10,353 VLBW infants from the Korean Neonatal Network database from January 2013 to December 2017. The dependent variable was NEC. Seventy-four predictors, including ambient temperature and particulate matter, were included. An artificial neural network, decision tree, logistic regression, naïve Bayes, random forest, and support vector machine were used to evaluate the major predictors of NEC. Among the six prediction models, logistic regression and random forest had the best performance (accuracy: 0.93 and 0.93, area under the receiver-operating-characteristic curve: 0.73 and 0.72, respectively). According to random forest variable importance, major predictors of NEC were birth weight, birth weight Z-score, maternal age, gestational age, average birth year temperature, birth year, minimum birth year temperature, maximum birth year temperature, sepsis, and male sex. To the best of our knowledge, the performance of random forest in this study was among the highest in this line of research. NEC is strongly associated with ambient birth year temperature, as well as maternal and neonatal predictors.