INTRODUCTION: Acute-on-chronic liver failure (ACLF) is a severe syndrome that manifests as acute liver function deterioration and organ failure. Coinfection with invasive pulmonary aspergillosis (IPA) in ACLF patients is characterized by high mortality and increasing morbidity. The aim of this study was to explore the early warning factors and prognosis of ACLF patients with IPA coinfection. METHODS: In this retrospective study, we collected clinical, biochemical, and microbiological data from patients with ACLF and IPA from May 2019 to May 2023. Univariable and multivariate analyses were used to identify independent risk factors for IPA in ACLF patients. Moreover, the area under the curve (AUC) and decision curve analysis (DCA) were used to evaluate the model performance. RESULTS: A total of 438 patients with ACLF were enrolled, 408 (93.2%) non-IPA patients and 30 IPA (6.8%) including 29 probable cases and one proven case. The 28-day case fatality rate (56.7% vs 29.4%) was higher in ACLF patients with IPA than in ACLF patients without IPA, but without statistical difference. Multivariate analysis revealed that early warning factors for IPA coinfection in ACLF patients included nausea ( CONCLUSION: These findings provide valuable insights for clinicians in the early diagnosis of IPA in ACLF patients and may facilitate timely intervention and treatment.