Introduction:Talaromyces marneffei is a pathogen that causes talaromycosis, a systemic fungal infection. Cases in which hepatic failure is the primary clinical presentation are exceedingly rare. Case Presentation: This report details the case of a 49-year-old male with no prior liver disease, presenting to the hospital with persistent symptoms, including a fever lasting over ten days, abdominal distension for five days, and jaundice for three days. The patient's history included immune thrombocytopenia and prolonged glucocorticoid therapy. Physical examination revealed yellowing of the skin and sclera, abdominal distension, firmness of the abdominal wall, absence of abdominal tenderness, positive shifting dullness, and pitting edema in the lumbosacral region and bilateral lower extremities. An HIV antibody test was negative. The patient developed hepatic failure and received artificial liver support along with routine therapy. Despite these interventions, the patient was automatically discharged without improvement and subsequently passed away. Post-discharge, cultures from pleural and abdominal effusions identified Talaromyces marneffei. Conclusions:Talaromyces marneffei infection should be considered in the differential diagnosis of immunocompromised patients, particularly those with no history of liver disease but with long-term glucocorticoid or immunosuppressant use who present with acute liver failure. Early and aggressive investigation for the causative pathogen is essential to minimize diagnostic and treatment delays. Given the prolonged incubation period of Talaromyces marneffei, metagenomic next-generation sequencing may offer a more rapid approach for etiological diagnosis.