Herpes simplex virus (HSV) is a common, easily transmissible virus. There is growing awareness of acyclovir-resistant HSV particularly among immunocompromised patients, which may be due to protracted treatments with guanosine analogues. Given the considerable morbidity associated with other classes of antiherpetic medications such as foscarnet (renal impairment, seizures) and cidofovir (renal impairment, neutropenia), imiquimod, a toll-like receptor agonist that enhances the innate immunologic responses against the virus, has been utilized in treating acyclovir-resistant HSV. We present a case of a human immunodeficiency virus (HIV)-positive patient who was successfully treated with topical imiquimod after treatment failures with other oral antivirals.