ABSTRACTBackgroundMpox (formerly known as monkeypox), a zoonotic disease caused by Monkeypox virus (MPXV), has become an international outbreak since May 2022. Mpox often presents with a mild systemic illness and a characteristic vesiculopustular skin eruption. In addition to molecular testing, histopathology of cutaneous lesions usually shows distinctive findings, such as epidermal necrosis, balloon degeneration, papillary dermal edema, and focal dermal necrosis, which have proven helpful in the diagnosis of mpox. Viral cytopathic changes with areas of multinucleation, smudging of the nuclei, and intracytoplasmic inclusions have also been described. Although useful, these features are relatively nonspecific. The use of a monoclonal antibody for immunohistochemical (IHC) staining of MPXV may be a useful tool in confirming mpox infection.MethodsThree cases of PCR‐confirmed mpox were biopsied and subjected to IHC staining with a monoclonal MPXV‐specific antibody targeting viral envelope protein A29. As controls, cell lines transduced to express other MPXV viral antigens and samples of cutaneous viral infections involving Molluscum contagiosum, Herpes simplex, Herpes zoster, or Cytomegalovirus were also subjected to IHC staining with this antibody.ResultsAll three mpox patient biopsies performed on lesional skin subjected to MPXV IHC staining reliably detected viral infection in lesional skin with a diffuse cytoplasmic and focally nuclear staining pattern. No staining was seen in transduced cell lines expressing off‐target MPXV viral antigens and in lesional skin of other common viral infections listed above.ConclusionsThe monoclonal MPXV‐specific antibody may be used as an adjunct tool to confirm mpox infection.