Invasive pulmonary aspergillosis (IPA) has been increasingly frequent in severe liver disease. We aim to investigate the clinical presentation, predisposing factors, and treatment of IPA in patients with liver failure caused by hepatitis B virus (HBV) infection. Medical records from 798 patients with HBV-related liver failure were reviewed. A total of 43 patients with probable IPA were selected as the case group, another 43 patients with bacterial infection and 43 patients without any infections were selected, for whose age, sex, date of admission, and the disease onset were matched with the case group. We evaluated the risk factors, clinical manifestations, treatment, and subsequent outcome of IPA in patients with HBV-related liver failure. Multivariate logistic regression models were used to demonstrate risk factors associated with IPA. Compared with patients with bacterial infection and those without any infection, patients with probable IPA used more antibiotics and steroids, and had poorer conditions and the highest mortality (P < 0.0001). Multiple antibiotics use and frequent invasive procedures were independent factors associated with the occurrence of IPA in patients with HBV-related liver failure. Patients with HBV-related liver failure are predisposed to IPA and may have a more severe condition and poorer prognosis.