A 70-year-old man with history of heart transplant performed in 1986, presented with altered mental status. CT scan of brain showed ring-enhancing lesions, raising suspicion for metastatic malignancy. Work-up revealed bilateral adrenal masses, biopsy showed granulomatous changes consistent with histoplasmosis. The possibility of histoplasmosis was less likely as the patient had no prior history of symptomatic disease and had lived in the endemic area 30 years prior to presentation. Brain biopsy confirmed central nervous system involvement. Amphotericin B was initiated for disseminated disease but his hospital course was complicated by renal failure and new liver hypodensities on follow-up imaging. Acute progressive disseminated histoplasmosis can manifest after decades of initial exposure and should always be in differential diagnosis even in non-endemic areas for prompt diagnosis and better clinical outcome.