Purpose: We aim to identify the predictors of respiratory distress syndrome, neonatal sepsis and mortality among preterm neonates admitted to neonatal intensive care unit at Ayder Comprehensive Specialized Hospital, northern Ethiopia. Materials and methods: An institutional-based retrospective cross-sectional study was conducted on 816 preterm neonates. An association between variables was decided at p-value <= 0.05. or AOR, 95% CI. Results: Neonatal sepsis was significantly associated with cesarean section (AOR = 0.62, CI (0.43-0.91)), male (AOR = 1.6, CI (1.12-2.28)), 4-6 APGAR score at 1-min (AOR = 1.67, CI (1.15-2.42)) and hospitalization for more than 14 days (AOR = 2.62, CI (1.5-4.58)) days. Also, the determinants of respiratory distress syndrome were compound fetal presentation (AOR = 2.17, CI (1-4.71)), < 28 weeks of gestational age (AOR = 3.32, CI (1.07-10.22)), 28-31 6/7 weeks of gestational age (AOR = 4.19, 0 (2.39-7.33)), 1-1.49 kg birth weight (AOR = 4.22, CI (1.79-9.93)) and 4-6 APGAR score at 1-min (AOR = 2.22, CI (1.54-3.19)). Respiratory distress syndrome (AOR = 12, CI (5.42-26.94)) and perinatal asphyxia (AOR = 3.42, CI (1.64-7.11)) were also associated with preterrn neonatal mortality. Conclusion: The predictors of respiratory distress syndrome were fetal presentation, gestational age, birth weight and 1st minute APGAR score. Also, neonatal sepsis was significantly associated with mode of delivery, sex, 1st minute APGAR score, respiratory distress syndrome and duration of hospitalization. Lastly, the predictors of mortality were respiratory distress syndrome, 1st minute APGAR score and perinatal asphyxia. Practice implications: It will give clues to mobilize resources towards the main predictors of comorbidity and mortality in preterms in the health care settings. (C) 2021 Elsevier Inc. All rights reserved.