Talaromyces marneffei infection is an endemic opportunistic infection for immunodepression patients, especially HIV-positive patients. Our case describes an unendemic and HIV-negative patient who presented with fever, subcutaneous mass, osteolytic destruction of the skull and subcutaneous abscess penetrating the diseased skull. The growth of Talaromyces marneffei was identified by the culture of the frontal pus, sputum, blood and bone marrow. Due to severe nausea and vomiting during the use of amphotericin B, voriconazole was finally selected for treatment. Two weeks after intravenous infusion of voriconazole injection, the patient was given oral voriconazole tablets for 5 months. After the initial intravenous treatment of voriconazole, the patient developed increased dyspnea and required ventilator support with endotracheal intubation, and methylprednisolone was given intravenously for 5 days. All lesions absorbed and no obvious discomfort was found during the follow-up at the third month after discharge. At present, the patient has been followed up for more than 3 years without recurrence. The case aims to raise doctors' awareness of this rare disease in non-endemic areas and HIV-negative patients.