Objective To study the predictive factors for poor prognosis of neonates with early-onset sepsis (EOS). Methods The clinical data of 371 neonates with EOS were collected. According to prognosis, they were divided into a good prognosis group with 264 neonates and a poor prognosis group with 107 neonates. The two groups were compared in terms of perinatal conditions, clinical manifestations, laboratory markers, comorbidities, and treatment process. Multivariate logistic regression analysis was used to investigate the predictive factors for poor prognosis of EOS. Results The poor prognosis group had significantly lower birth weight and gestational age than the good prognosis group (P < 0.05). Compared with the good prognosis group, the poor prognosis group had significantly higher proportions of preterm neonates, low birth weight neonates, very low birth weight neonates and twins (P < 0.05), as well as a significantly higher proportion of mothers who used hormone or antibiotics before delivery (P < 0.05). Compared with the good prognosis group, the poor prognosis group had significantly higher incidence rates of poor response and respiratory hypofunction (P < 0.05) and a significantly lower incidence rate of jaundice (P < 0.05). Compared with the good prognosis group, the poor prognosis group had significantly higher incidence rates of white blood cell count <5×10⁹/L, platelet count <100×10⁹/L, anemia, coagulation disorder, renal dysfunction, liver impairment, hypoproteinemia, and hypoglycemia (P < 0.05). The poor prognosis group had significantly higher incidence rates of neonatal respiratory distress syndrome, pulmonary hemorrhage, necrotizing enterocolitis, intraventricular hemorrhage, brain injury, pulmonary hypertension, and shock than the good prognosis group (P < 0.05). Compared with the good prognosis group, the poor prognosis group had significantly longer length of hospital stay and course of treatment with antibiotics (P < 0.05) and a significantly higher proportion of neonates receiving mechanical ventilation or vasoactive agents (P < 0.05). The multivariate logistic regression analysis showed that very low birth weight (OR=41.734), necrotizing enterocolitis (OR=12.669), brain injury (OR=8.372), shock (OR=5.889), mechanical ventilation (OR=5.456), and liver impairment (OR=4.075) were independent predictive factors for poor prognosis of neonates with EOS (P < 0.05). Conclusions Very low birth weight, mechanical ventilation, necrotizing enterocolitis, brain injury, shock, and liver impairment have a certain value in predicting the poor prognosis of neonates with EOS.