This case report describes an atypical presentation of a relatively common opportunistic infection, without documented exposure to areas known at the time to be endemic, resulting in catastrophic complications. The patient presented with a two month progressive history of vomiting, diarrhea, productive cough, and shortness of breath, on the background of poorly-controlled HIV. There was a low index of suspicion for infection with histoplasmosis, particularly given the large differential diagnosis and the lack of travel or endemic precedence. The case was complicated by the development of disseminated intravascular coagulation (DIC) prior to identification of the pathogen. Ultimately, the patient's goals of care transitioned to palliation, and treatments were discontinued. It is our hope that in the future, such outcomes might be prevented by considering disseminated histoplasmosis in systemically unwell patients with HIV, regardless of endemic exposure or specific presentation.