Syphilis sero-resistance is a special phenomenon in sera-resistant syphilis patients after anti-syphilis treatment, also known as sero-resistant syphilis. The pathogenesis of sero-resistance syphilis has not yet been clearly understood, and the clinical prognosis of the patients is often uncertain. It has become an important issue in prevention and control of syphilis, especially in the clinical diagnosis and anti-syphilis treatment. Related studies have shown that sero-resistance occurs frequently in female syphilis patients older than 40 years, and is related to the anti-syphilis medications, dosages, and treatment methods. It is also closely related to treponema pallidun (TP)-associated HIV infection and rapid plasma regain test (RPR) serum titers. In addition, the correlation between immunological infection mechanisms (infection and immunity, immunosuppression, autoimmunity, etc.) and syphilis sero-resistance is also notable. Cell-mediated immunity and antibody-mediated humoral immunity may play an equally important role in the immunological mechanism of syphilis sero-resistance and should be an important research direction. In-depth studies on the mechanism of syphilis sero-resistance have important clinical significance and laboratory diagnostic significance.