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Background: Syphilis is a sexually transmitted infection (STI) with a global prevalence estimated at 0.5% in 2012. Syphilis has been on the rise among men who have sex with men (MSM) in high‐income countries and remains at endemic levels in low‐ and middle‐income countries. This trend, however, has not been observed in Reunion Island. Objectives: To determine the prevalence, clinical characteristics and risk factors of syphilis in at‐risk patients visiting the South Reunion STI clinic in Reunion Island. Methods: This monocentric cross‐sectional study included all patients who visited our STI clinic between 2017 and 2020. Syphilis serology was performed on all included patients, and data were collected using a standardized self‐administered questionnaire. Results: Over the 3‐year study period, 2593 patients were enrolled. The prevalence of syphilis was 7.52% (n = 195, 95% CI, 6.50–8.65%) in the overall study population, 11.76% (n = 18, 95% CI, 6.97–18.59%) in minors (aged under 18 years) and 36.36% (n = 16, 95% CI, 21–59%) in pregnant women. The risk factors identified in multivariate analysis were being female [adjusted Prevalence Ratio (aPR) 1.85, 95% CI, 1.10–3.11], being MSM (aPR 2.87, 95% CI, 1.71–4.80), being aged under 18 years (aPR 3.54, 95% CI, 1.90–6.57), living in precarious conditions [aPR 3.12, 95% CI, 2.11–4.62] and being born in Reunion Island (aPR 2.43, 95% CI, 1.42–4.13). The clinical presentation was heterogeneous (plaques and papules, chancre, atypical ulcerations, multiple ulcerations, condyloma lata, etc.). Conclusions: These findings suggest a high prevalence of syphilis in at‐risk patients visiting our STI clinic. Unlike the situation in other high‐income countries, the people most at risk of syphilis in Reunion Island are local‐born residents, minors, women and precarious patients. This is a source of concern, especially given the risk of resurgence of congenital syphilis on the island. [ABSTRACT FROM AUTHOR]