 A 33-year-old man in Baltimore, Maryland, USA, with untreated HIV infection had a 74-day course of Mpox with multi-organ system involvement and unique clinical findings. In this clinical experience combining three novel therapeutic regimens, this patient died from severe Mpox in the context of untreated HIV and advanced immunodeficiency. This article was authored by Yevgeniy Filippov, Sunchit Duhan, Laura Lehman, and others.