BACKGROUND: Histoplasmosis is a rare infectious condition with mainly pulmonary involvement which is generally self-limiting in immunocompetent individuals. Its manifestation varies and lacks specificity. This study reports a case of primary disseminated liver histoplasmosis in a normal host presenting as liver failure cured by liver transplantation and voriconazole. CASE SUMMARY: A 43-year-old Chinese man with intermittent fever, malaise, jaundice and extreme hepatomegaly for more than 40 days was admitted to the Second Xiang-ya Hospital. The patient was immunocompetent and lacked a definitive history of exposure. His condition deteriorated to liver failure, and he promptly underwent liver transplantation to ensure survival. One year later, the patient presented with severe gastrointestinal symptoms, including fever, abdominal pain, and diarrhea. Subsequently, tissue samples acquired CONCLUSION: In patients with chronic-hepatitis-B having atypical symptoms, histoplasmosis can be a differential diagnosis. Voriconazole is effective in treating histoplasmosis.