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While New Materialism and Object Oriented Ontology have provided frameworks to consider human relationships to nonhuman beings and objects in the twenty-first century, scientists and authors explored similar ethical dilemmas brought about by the newly identified presence of microorganisms in what had previously been imagined as a human world at the turn of the twentieth century. This essay considers Mark Twain's later fiction alongside the work of American bacteriologist Herbert W. Conn. Already invested in undermining human exceptionalism through scalar differences in his Mysterious Stranger manuscripts (1897–1908), Twain adapts Conn's bacteriology to experiment with microbial ethics in Three Thousand Years Among the Microbes (1905). While Conn uses microbes to assert scientific mastery and professional authority, Twain uses them to experiment with ethical structures on nonhuman scales. I argue that the failures of Twain's imaginative experiment dramatize the practical challenges to radically inclusive ethical structures proposed by New Materialists and others.