Syphilis, a prevalent sexually transmitted infection, presents significant diagnostic complexities, particularly among people living with human immunodeficiency virus (PLWH) and men having sex with men. In recent years, a surge in global syphilis cases has been observed, including Central and Eastern Europe countries. Atypical manifestations of syphilis commonly make diagnosis more difficult, with syphilitic hepatitis being a rare but a noteworthy example. Non-specific symptoms, specifically in secon­dary and tertiary syphilis, often lead to syphilis not being included in differential diagnoses. This paper described syphilis epidemiology in Poland. One of the most difficult clinical manifestation is syphilitic hepatitis, typically occurring in early syphilis. It manifests with various symptoms, such as rash, fatigue, hepatomegaly, jaundice, lymphadenopathy, and elevated liver enzymes. Diagnostic criteria include abnormal liver enzymes, serological evidence of Treponema pallidum infection, exclusion of other causes, and enzyme normalization post-antibiotic therapy. In rare cases, syphilitic hepatitis progresses to hepatic gummas, which imitate metastases. Syphilitic gastritis, nephritis, arthritis, and atypical cutaneous manifestations, more prevalent in PLWH, challenge the correct diagnosis further. HIV co-infection can alter syphilis progression, with simultaneous primary and secondary eruptions, larger and more numerous primary lesions, aggressive secondary syphilis, neurological complications, and an increased incidence of syphilis with unclear clinical picture. Syphilis can be a diagnostic challenge due to its multi-faceted clinical manifestations and potential aty­pical course, especially among PLWH. Healthcare providers must include syphilis and sexual history into differential diagnoses in cases with organ or systemic disorders of unclear origins, even in indivi­duals without apparent sexual risk factors.