Cytomegalovirus is a DNA virus that belongs to the β-herpesvirus family. Most of the infections are asymptomatic and persist for the whole life, being frequently considered harmless in healthy individuals. Symptomatic infection in immunocompetent individuals may occur most commonly among infants, usually as a mononucleosis-like syndrome with fever, malaise, lymphadenopathy, and mild hepatitis. In immunosuppressed patients, cytomegalovirus infection represents a potential life-threatening opportunistic infection. Transmission occurs by different routes, including vertical transmission via the placenta, birth canal, and/or breast milk; horizontal transmission through saliva, urine, semen, blood, and/or cervical or vaginal discharge; or organ transplantation. In the oral cavity, cytomegalovirus can be isolated from healthy mucosa, saliva, and periodontal pockets. Oral lesions most often present as nonspecific ulcers, more often in the lips, palate, tongue, and gingiva. These ulcers are usually shallow with well-defined borders and an overlying yellowish pseudomembrane. Microscopic diagnosis of these oral lesions frequently demands from pathologists a high level of diagnostic suspicion due to their nonspecific inflammatory infiltrate containing lymphocytes, macrophages, and neutrophils. Infected cells are large (cytomegaly), with nuclei containing viral inclusions, which can be demonstrated by immunohistochemistry. Symptomatic infection is considered a self-limited condition, but immunocompromised patients should have their immunological state corrected.