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<i>Acanthamoeba</i> is well known to host a variety of microorganisms such as viruses, bacteria, protozoa, and yeast. Given the recent number of cases of monkeypox infection, we speculate that amoebae may be aiding viral transmission to the susceptible hosts. Although there is no confirmatory evidence to suggest that <i>Acanthamoeba</i> is a host to monkeypox (a double-stranded DNA virus), the recent discovery of mimivirus (another double-stranded DNA virus) from <i>Acanthamoeba</i>, suggests that amoebae may shelter monkeypox virus. Furthermore, given the possible spread of monkeypox virus from animals to humans during an earlier outbreak, which came about after patients came in contact with prairie dogs, it is likely that animals may also act as mixing vessel between ubiquitously distributed <i>Acanthamoeba</i> and monkeypox virus, in addition to the environmental habitat that acts as an interface in complex interactions between diverse microorganisms and the host.