Relevance. This study is relevant as the incidence of late neurosyphilis increased in recent years and ceftriaxone is frequently used to treat this disease without studying the efficacy of this drug compared to penicillin. Objective. The objective of the investigation was to conduct such a comparative study. Material and methods. The paper reports the results of treatment of 58 patients with late neurosyphilis, both asymptomatic one (n=31) and with symptoms (n=27), using ceftriaxone compared to the results of treatment of these forms of syphilis with penicillin. Both drugs were administered intravenously. Results. It has been found that the effectiveness of the two methods is almost equivalent in the case of asymptomatic neurosyphilis. In the case of meningovascular form of the disease, the patients who received ceftriaxone often require additional treatment to achieve the effect (regression of clinical symptoms and clearing of the CSF). In patients with progressive paralysis, it is not always possible to achieve clearance of the SCF and regression of clinical symptoms using ceftriaxone. Conclusions. The effectiveness of treatment of late asymptomatic and meningovascular neurosyphilis with ceftriaxone and penicillin is comparable, while in the case of progressive paralysis, penicillin is more effective. Patients who had late neurosyphilis with symptoms and were treated with ceftriaxone, often required an additional treatment along with the basic one. Considering this, the authors believe that the use of ceftriaxone in patients with late neurosyphilis who are not allergic to penicillin is not advisable.