In May 2022, a cluster of non-travel-related cases of human mpox were reported in the UK. The outbreak has since spread world-wide infecting over 85,000 patients and causing over 100 deaths. Recent data clearly suggest that patients infected with Human Immunodeficiency Virus (HIV) with CD4 counts less than 200 cells per mm 3 suffer significantly worse outcomes than immunocompetent patients. The available countermeasures lack robust clinical data and are deployed based on in vitro and animal studies as well as extrapolations from use against other poxviruses. In many cases, despite administration of these available treatments, initiation of antiretroviral therapy, and management of Immune Reconstitution Inflammatory Syndrome (IRIS), patients die. This review summarizes available data, identifies knowledge gaps and proposes recommendations on the management of severe mpox in PLWH.