BACKGROUND: Syphilis remains a global health challenge, with rising incidence rates worldwide Prevalence surveys conducted in Brazil over extended periods of time are scarce. This study examines the secular trends and risk factors for syphilis seroprevalence among first-time blood donors in Brazil. METHODS: A retrospective analysis was conducted as part of a multicenter, repeated cross-sectional survey of blood donors from four major Brazilian blood centers, covering the period from 2007 to 2020. First-time donors who had undergone valid treponemal screening tests were included in the final dataset. Demographic characteristics and serological results were analyzed to identify risk factors for syphilis seroprevalence using multivariate Poisson models. An interaction term between age group and donation year was added to the final model. Model comparisons were performed using Likelihood Ratio Tests (LRT) and Akaike Information Criterion (AIC). RESULTS: 1,424,850 donations from first-time donors were included during the study period. The overall syphilis seroprevalence was 2.19%, with significant heterogeneity across centers. Risk factors for increased seroprevalence included male gender, older age, lower education level, and self-reported black or mixed skin color. Notably, an increasing trend in syphilis seroprevalence was observed among younger donors and those born after 1990. Interaction analyses revealed significant effects between visit period and key demographic variables (age group, gender, education, and ethnicity), with the interaction between age group and donation year indicating higher seroprevalence among younger age groups in recent years. CONCLUSION: The study highlights a high syphilis seroprevalence among first-time blood donors in Brazil, which has significant implications for blood safety and public health. The increasing trend among younger donors suggests a shift towards newer infections, warranting continued surveillance in this demographic.