Objective To investigate the risk factors of neonatal acute bilirubin encephalopathy. Methods From February 2013 to October 2015, 58 neonates with acute bilirubin encephalopathy (study group) and 58 neonates without bilirubin encephalopathy (control group) in our hospital were enrolled in the study. The general data, complications and laboratory tests were observed and compared between the two groups. The risk factors of neonatal acute bilirubin encephalopathy were analyzed and summarized. Results The gestational age and percentage of cases with asphyxia showed no significant differences between the two groups (P>0.05). The birth weight of study group was significantly lower than that of control group while the total bilirubin peak was significantly higher. The percentages of cases with jaundice in 12 hours, G-6-PD deficiency, infection, neonatal hemolysis, metabolic acidosis and hypoproteinemia in the study group were significantly higher than those in the control group (P<0.05). Conclusion Low birth weight, high total bilirubin peak, incidence of jaundice within 12 hours, G-6-PD deficiency, infection, neonatal hemolysis, metabolic acidosis and hypoproteinemia are the risk factors for neonatal acute bilirubin encephalopathy.