Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG) infections are common among men who have sex with men (MSM). Many oropharyngeal and anorectal infections remain asymptomatic. We aimed to evaluate triple-site screening following PrEP introduction. We enrolled a prospective cohort study including 210 asymptomatic MSM during 2019–2020, analyzed by groups: HIV positive (HIV+), HIV−uninfected using PrEP (HIV−/PrEP+), or HIV-uninfected not using PrEP (HIV−/PrEP−). A self-administered questionnaire captured demographic information and sexual risk-taking behaviors. CT/NG testing results were compared between study groups and predictors of infection were evaluated. We included 59 HIV+, 70 HIV−/PrEP+, and 81 HIV−/PrEP− subjects. 30% ( n = 62) of participants tested positive for CT/NG. HIV−/PrEP+ group had highest proportion of infections ( n = 33, 47%) followed by HIV−/PrEP− ( n = 16, 22%) and HIV+ ( n=13, 20%; p < .001). Importantly, 98% (80/82) of pharyngeal/anorectal CT/NG infections were missed in genitourinary tract screening alone. PrEP use and previous syphilis infection were the strongest risk factor for CT/NG. Extra-genital asymptomatic CT/NG infections were prevalent among MSM. These data highlight the importance of routine extra-genital CT/NG testing in asymptomatic sexually active MSM. The study describes the consequences for three-site testing lack of implementation in the PrEP era.