Background: Recommendations for sexually transmitted infection (STI) screening vary significantly across countries. This study evaluated the prevalence of urogenital and extragenital infections with Chlamydia trachomatis (CT), Neisseria gonorrhoeae (NG), and Mycoplasma genitalium (MG) in patients visiting a French STI clinic in the Indian Ocean region to determine whether current STI screening practices should be updated. Methods: This cross-sectional study examined all patients who visited the STI clinic between 2014 and 2015. Triplex polymerase chain reaction screening for CT, NG, and MG was performed on urine, vaginal, pharyngeal, and anal specimens (FTD Urethritis Basic Kit, Fast Track Diagnostics, Luxembourg). Results: Of the 851 patients enrolled in the study, 367 were women (367/851, 43.2%) and 484 were men (484/851, 56.0%). Overall, 826 urogenital specimens (826/851, 97.1%), 606 pharyngeal specimens (606/851, 71.2%), and 127 anal specimens (127/851, 14.9%) were taken from enrolled patients. The prevalence of urogenital CT and MG was high in women ≤25 years (19/186, 10.21%; 5/186, 2.69%) and in men who have sex with women ≤30 years (16/212, 7.54%; 5/212, 2.36%). Among patients with urogenital CT infection, 13.7% (7/51) had urethritis. All patients with urogenital MG infection were asymptomatic. Men who have sex with men had a high prevalence of pharyngeal CT (2/45, 4.44%) and NG (3/44, 6.81%) and a high prevalence of anal CT (2/27, 7.41%), NG (2/27, 7.40%), and MG (1/27, 3.70%). After excluding patients with concomitant urogenital infection, extragenital infections with at least 1 of the 3 pathogens were found in 20 swabs (20/91, 21.9%) taken from 16 patients (16/81, 19.7%), all of them asymptomatic. Conclusions: Routine multisite screening for CT, NG, and MG should be performed to mitigate the transmission of STIs in high-risk sexually active populations.