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Mpox, caused by infection with Monkeypox virus, usually presents as a mild, self-limited illness in immunocompetent persons that resolves within 2–4 weeks. Serious complications have been reported when mpox lesions involve vulnerable anatomic sites, such as the eye, and in those with substantial immunosuppression. We describe a patient with advanced human immunodeficiency virus infection and sustained viral shedding of mpox with ocular involvement, which resulted in vision loss.