Histoplasma capsulatum (HC) is a thermally dimorphic ascomycete that is a significant cause of respiratory infections (>80%) in endemic areas (Midwest and southeast USA), but infections are rare in non-endemic areas. Most primary HC infections are subclinical or self-limited. While reactivation Histoplasmosis has been reported in the setting of immunosuppression, it remains unclear whether remote primary latent infection represents risk of endogenous reactivation after anti-tumor necrosis factor (TNF)-alpha therapy. We report a case of a patient who developed reactivation Histoplasmosis after receiving anti-TNF-alpha. To our knowledge, this is the first clear report of reactivation of "latent" Histoplasmosis after anti-TNF-alpha therapy.