Adult-onset acquired immunodeficiency caused by anti-IFN-γ autoantibodies is associated with severe opportunistic infection. Due to lack of specific symptoms and different manifestations, this form of infection can be easily misdiagnosed or overlooked. Herein, we present a case of Nocardia farcinica and Talaromyces marneffei co-infection in a patient with anti-IFN-γ autoantibodies (AIGAs). The patient, a 54-year-old man, presented with a 1-month history of fever, coughing and expectoration, dizziness, headache and gait imbalance. Laboratory workup revealed increased inflammatory markers, negative anti-HIV antibody and a high positive titer of AIGAs. Chest computed tomography (CT) showed multiple patches of high-density shadows in both lungs, and brain enhanced magnetic resonance imaging (MRI) showed an irregular lesion. The patient underwent a craniotomy for resection of the lesion. Pulmonary T. marneffei infection was diagnosed through sputum and bronchoalveolar lavage fluid culture, and brain nocardiosis was confirmed via purulent fluid culture of brain tissue. With regular antibiotic therapy, his symptoms improved and there was no recurrence during 18-month follow-up. This may be the first detailed case report detailing infection with these two distinct pathogens in disparate anatomical locations.