AbstractWe report a case of a 42‐year‐old immunocompromised (human immunodeficiency virus [HIV], CD4 count 86 cells/μL) Black male who presented with fever, oropharyngeal candidiasis, and phimosis, followed by eruption of umbilicated papulovesicles most concentrated on the face. The patient was diagnosed with Mpox (MPXV, formerly monkeypox), herpes simplex virus 1 (HSV1), varicella‐zoster virus (VZV), and late latent syphilis. Tzanck smear of a Mpox lesion proved a useful and rapidly obtained pertinent negative test, lacking the typical changes of HSV/VZV (multinucleation, margination, and molding). A biopsy specimen showed viral changes consistent with both Mpox (ballooning degeneration and multinucleated keratinocytes) and herpesvirus (multinucleated epithelial giant cell within a zone of follicular necrosis). Lesion PCR was positive for HSV1 and MPXV, and negative for HSV2 and VZV. Immunohistochemistry was positive for VZV and orthopoxvirus. Empiric treatment for HSV/VZV in patients with suspected or confirmed Mpox should be considered for patients with HIV or other immunocompromised patients. It is important to recognize that MPXV, HSV, and VZV may all be present and difficult to distinguish clinically. More than one test modality (PCR, H&E, immunohistochemistry, and Tzanck) and multiple lesion samples may be required to thoroughly evaluate widespread papulovesicular eruptions, especially in immunocompromised patients.