Franklin disease, or gamma heavy-chain disease, in patients with autoimmune disorders is a challenge for clinicians to diagnose due to its rarity, and recurrent infection is one of its characteristics. Within the spectrum of infections in Franklin disease patients, various fungi should always be considered. In this study, the authors describe a 57-year-old non-human immunodeficiency virus-infected systemic lupus erythematosus patient later diagnosed with Franklin disease and then developed Penicillium pneumonia. Because of the unexpected combination of Franklin disease and Penicillium infection in a non-human immunodeficiency virus-infected patient, the diagnosis of common hospital-acquired pneumonia was initially made. The laboratory examinations and cultures helped confirm the correct diagnosis of Franklin disease and Penicillium pneumonia. This is the first report of Penicillium sp. infection in a patient with Franklin disease, and it emphasizes the importance of proper preparation for biopsy, complete hematologic investigation, culture preparation and early antifungal coverage to improve the outcome.