Antiprotozoal screening tests on a large number of nitroimidazoles provided four new compounds for extensive comparative evaluations with two known, substituted 5-nitroimidazoles. Studies have shown there are only minor or no differences in the concentrations required of these compounds for inhibiting the in vitro growth of Trichomonas foetus or Entamoeba histolytica. However, in respect to therapeutic potency, marked differences were observed for these compounds in controlling experimental trichomoniasis and amebiasis. Ronidazole and “MF” nitroimidazole were several-fold more potent than metronidazole and dimetridazole in the treatment of T. foetus infections in mice. “MF” nitroimidazole was also the most potent compound for controlling experimental intestinal amebiasis in rats. Although “MCA” nitroimidazole was the least potent in the control of amebaisis, this compound was clearly the most potent compound for controlling highly lethal Trypanosoma brucei infections in mice. These studies show that the antiprotozoal spectrum and potency of substituted 5-nitroimidazoles may vary greatly with minor changes in the molecule. They further demonstrate that highly potent therapeutic agents can be obtained by systematically modifying the structure of these compounds to achieve specific antiprotozoal action. These highly potent 5-nitroimidazoles appear worthy of clinical evaluation as potentially useful agents for the therapy of trichomoniasis, amebiasis, and trypanosomiasis.