Low efficacy has been reported for the treatment of with antimicrobial agents other than the 5-nitroimidazole class. Patients with immunoglobulin E (IgE)-mediated hypersensitivity reactions to drugs in this class, including metronidazole and tinidazole, may benefit from a desensitization treatment. We present two patients with past medical histories of IgE-mediated hypersensitivity reactions to metronidazole who were successfully treated with metronidazole using a modified protocol. The first patient was a 39-year-old female diagnosed with trichomoniasis who had a previous reaction to metronidazole characterized by urticaria and pruritus. The second patient was a 53-year-old female who had a history of untreated trichomoniasis due to a previous anaphylactic reaction to metronidazole. Both patients were successfully treated in the intensive care unit (ICU) without signs and symptoms of the reaction. Physicians may use a desensitization protocol for patients with a presumed IgE-mediated hypersensitivity when only the 5-nitroimidazole class is efficacious for the treatment of trichomoniasis.