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Neng Wang,* Conglin Zhao,* Congchen Tang, Lichun Wang Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, People’s Republic of China*These authors contributed equally to this workCorrespondence: Lichun Wang, Center of Infectious Diseases, West China Hospital of Sichuan University, 37 Guoxue Lane, Chengdu, 610041, People’s Republic of China, Tel +86 288 542 2859, Fax +86 288 542 3052, Email mindywang0218@163.comBackground: Histoplasmosis is a deep fungal infection caused by Histoplasma capsulatum and can be classified as pulmonary, disseminated or central. Disseminated histoplasmosis is the most dangerous of all clinical types and is characterized by rapid onset, rapid progression, high mortality, and difficulty in diagnosis and treatment.Case Presentation: This report describes a 31-year-old female who presented with fever, with a maximum temperature of 39.8 °C. There were no concomitant symptoms, such as cough, sputum, abdominal pain and diarrhoea, before the onset of fever, and the illness lasted for more than 20 days. On examination, the liver and spleen were enlarged, and laboratory tests showed a significant decrease in CD4 cell count, suggesting immune deficiency. Broad-spectrum antibiotic treatment was ineffective, and specific infectious diseases and haematological neoplasms were considered likely. She was finally diagnosed with disseminated histoplasmosis after undergoing bone marrow aspiration and metagenomic next-generation sequencing (mNGS) and was treated with amphotericin B, fluorouracil and itraconazole, with good results.Conclusion: This case demonstrates that disseminated histoplasmosis infection can present with unexplained fever and that mNGS can be an important complement to bone marrow aspiration for the diagnosis of this disease.Keywords: disseminated histoplasmosis, immune deficiency, metagenomic next-generation sequencing, amphotericin B, case report