What is already known about this topic? Severe manifestations of monkeypox in immunocompromised persons have been observed in previous outbreaks. What is added by this report? During August-October 2022, CDC provided clinical consultation for 57 hospitalized patients with severe manifestations of monkeypox, most of whom were Black men with AIDS. Delays were observed in initiation of monkeypox-directed therapies. Twelve patients died, and monkeypox was a cause of death or contributing factor in five patients to date, with several other deaths still under investigation. What are the implications for public health practice? Clinicians should consider early treatment with available therapeutics for those at risk for severe monkeypox disease, particularly patients with AIDS. Engaging all persons with HIV in care remains a critical public health priority.