Syphilis has become popular again in China in the last 20 years, and despite the epoch-making impact of the advent of penicillin on the treatment of syphilis, reports of neurosyphilis are increasing day by day. This is due to the complex and variable clinical manifestations of neurosyphilis so far, the absence of the best diagnostic and differential diagnostic tools, and the absence of a vaccine to prevent it. Neurosyphilis is a disease caused by syphilis spirochetes attacking the nervous system. The incidence of neurosyphilis is 10% of that of syphilis. In the past, it was thought that neurosyphilis could only occur in stage III syphilis, but studies have found that syphilis spirochetes can be found in the lymph nodes minutes after inoculation and can spread throughout the body with the bloodstream within hours. It has also been shown that central nervous system (CNS) damage can occur in all stages of syphilis, although most of these cases are asymptomatic. Recent studies have shown that a rapid plasma reactin (RPR) ring card test titer ≥1:32 correlates with the development of neurosyphilis, regardless of the presence or absence of human immunodeficiency virus infection or the stage of syphilis. According to Wilson’s classification, neurosyphilis is divided into 10 main types, namely: 1. syphilitic meningitis (spinal); 2. spinal syphilis; 3. cerebral syphilis; 4. cerebrospinal syphilis; 5. spinal cord consumption; 6. generalized paralytic dementia; 7. syphilitic psychoneuropathy; 8. syphilitic neuritis; 9. syphilitic osteitis of the skull and spine; 10. congenital neurosyphilis. The clinical manifestations of neurosyphilis are neither heterogeneous, nor is there a gold standard for diagnosis, and its diagnosis cannot be based on one test alone, therefore, the diagnosis of neurosyphilis is still a medical problem. Currently, the diagnostic criteria for neurosyphilis include positive syphilis serology, abnormal cerebrospinal fluid cell count or protein assay results, and a positive VDRL test with or without clinical manifestations. Of these, the VDRL test has high specificity but low sensitivity, and the cerebrospinal fluid VDRL test may also be negative in the presence of neurosyphilis. The fluorescent spirochetal antibody absorption test (FTA-ABS) of cerebrospinal fluid is highly sensitive; therefore, a negative FTA-ABS test of cerebrospinal fluid can be used to rule out neurosyphilis. Both can have false positive reactions. It must be noted that imaging tests for CNS, including magnetic resonance imaging (MRI) angiography, computed tomography (CT) and isotope scan (SPECT), are not specific for the diagnosis of neurosyphilis, but may be useful in determining the prognosis of neurosyphilis. As Fleming predicted, penicillin is the best drug to treat syphilis. Because the most common drug for treating syphilis, benzathine penicillin, is not measured in CSF, it cannot be used in the treatment of neurosyphilis. Aqueous penicillin is currently the best choice for the treatment of neurosyphilis, and the commonly used dose for adults is aqueous crystalline penicillin G, 18-24 million U/d, intravenous 3-4 million U/4h or continuous IV for 10-14 d. Since the division of syphilis spirochetes is slower after treatment with penicillin, continue with benzathine penicillin 2.4 million U, intramuscular injection after the above treatment , 1 time/week for 3 times. In case of penicillin allergy, the following drugs can be considered as substitutes: ceftriaxone sodium (note that there may be cross-allergy with penicillin), doxycycline, minocycline, tetracycline hydrochloride, erythromycin, etc.