Syphilis, caused by Treponema pallidum, is a sexually and vertically transmitted infection exploiting antigenic variation (e.g., TprK proteins) to evade host immunity and persist. Global incidence is rising, especially among men who have sex with men and HIV-infected individuals, where prevalence exceeds 10% and 20%, respectively. Secondary syphilis presents diverse cutaneous and mucosal lesions, earning the moniker “the great imitator.” Accurate diagnosis requires combined serological testing, direct detection methods (e.g., PCR), and histopathology, crucial for identifying atypical presentations and managing immunocompromised patients.