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ABSTRACTInfections with Giardia lamblia, Entamoeba histolytica, and Trichomonas vaginalis, which cause diarrhea, dysentery, and vaginitis, respectively, are each treated with metronidazole. Here we show that Giardia, Entamoeba, and Trichomonashave oxygen-insensitive nitroreductase (ntr) genes which are homologous to those genes that have nonsense mutations in metronidazole-resistant Helicobacter pyloriisolates. Entamoebaand Trichomonasalso have nimgenes which are homologous to those genes expressed in metronidazole-resistant Bacteroides fragilisisolates. Recombinant Giardia, Entamoeba, and Trichomonasnitroreductases used NADH rather than the NADPH used by Helicobacter, and two recombinant Entamoebanitroreductases increased the metronidazole sensitivity of transformed Escherichia colistrains. Conversely, the recombinant nitroimidazole reductases (NIMs) of Entamoebaand Trichmonasconferred very strong metronidazole resistance to transformed bacteria. The Ehntr1gene of the genome project HM-1:IMSS strain of Entamoeba histolyticahad a nonsense mutation, and the same nonsense mutation was present in 3 of 22 clinical isolates of Entamoeba. While ntrand nimmRNAs were variably expressed by cultured Entamoebaand Trichomonasisolates, there was no relationship to metronidazole sensitivity. We conclude that microaerophilic protists have bacterium-like enzymes capable of activating metronidazole (nitroreductases) and inactivating metronidazole (NIMs). While Entamoebaand Trichomonasdisplayed some of the changes (nonsense mutations and gene overexpression) associated with metronidazole resistance in bacteria, these changes did not confer metronidazole resistance to the microaerophilic protists examined here.