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Progressive disseminated histoplasmosis is a disease where Histoplasma capsulatum affects multiple organs due to the inability of host cellular immunity to control the infection. Progressive disseminated histoplasmosis mainly involves the bone marrow, liver, and lungs. We report an unusual initial presentation of progressive disseminated histoplasmosis presenting as acute tenosynovitis in a systemic lupus erythematosus (SLE) patient. This report highlights the point that H. capsulatum may present as focal lesions and a high level of suspicion is needed to make the diagnosis, especially in SLE patients. We specifically reviewed reported cases of progressive disseminated histoplasmosis in SLE patients, and a review of the literature is presented.