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Two main routes of human herpesvirus 8 (HHV-8) transmission are known: sexual, predominantly in men who have sex with men; and nonsexual, in endemic populations. Both routes implicate saliva, so identifying the factors that influence oral HHV-8 shedding is important.Using polymerase chain reaction and immunohistochemistry, we prospectively analyzed HHV-8 infection of oral epithelial cells in 98 Swiss HIV Cohort Study patients, with mean follow-up of 9.4 years, and correlated data to immune status, HHV-8 serology, and Kaposi sarcoma (KS) history, as well as survival.Sixty-eight (43.9%) of the 98 men were HHV-8 seropositive, and 33 (33.67%) had a history of KS. In both groups, men who have sex with men were significantly more affected than heterosexuals (P < 0.05). Of 77 patients, 9 (11.6%) were oral HHV-8 polymerase chain reaction positive, and 2 of these were also positive by immunohistochemistry. Oral HHV-8 detection was not influenced by the immune status, but a trend toward higher detection was observed in patients with KS (P = 0.084). Oral HHV-8 shedding had no predictive value either for the development of KS lesions or for survival.Human herpesvirus 8 can be present in oral epithelial cells and is shed independent of the patient's immune status, indicating that oral HHV-8 shedding may occur at any time in HHV-8-seropositive individuals.