This study examines the atypical manifestations of syphilis in a 10-year retrospective analysis of 307 patients diagnosed at the University of Genoa and University of Foggia STI centers. The research aimed to analyze the correlations between atypical manifestations and demographic, clinical, and laboratory features of patients, as well as to review unusual presentations of syphilis reported in the literature. Atypical manifestations were detected in 25.8% of patients, particularly in the secondary stage of the disease. Common atypical presentations included annular lesions and itchy erythematous scaly plaques with psoriasiform appearance. Statistical analysis revealed that homosexual orientation, syphilis reinfection, and VDRL titers > 1:32 were correlated with atypical manifestations. The study highlights the wide spectrum of syphilis manifestations and the diagnostic challenges posed by atypical presentations, which can delay appropriate treatment and facilitate infection spread. Given the increasing incidence of syphilis, clinicians should maintain high clinical suspicion and recognize atypical presentations at any stage of the disease.This study examines the atypical manifestations of syphilis in a 10-year retrospective analysis of 307 patients diagnosed at the University of Genoa and University of Foggia STI centers. The research aimed to analyze the correlations between atypical manifestations and demographic, clinical, and laboratory features of patients, as well as to review unusual presentations of syphilis reported in the literature. Atypical manifestations were detected in 25.8% of patients, particularly in the secondary stage of the disease. Common atypical presentations included annular lesions and itchy erythematous scaly plaques with psoriasiform appearance. Statistical analysis revealed that homosexual orientation, syphilis reinfection, and VDRL titers > 1:32 were correlated with atypical manifestations. The study highlights the wide spectrum of syphilis manifestations and the diagnostic challenges posed by atypical presentations, which can delay appropriate treatment and facilitate infection spread. Given the increasing incidence of syphilis, clinicians should maintain high clinical suspicion and recognize atypical presentations at any stage of the disease.