Analysis of scientific publications and authors’ own experience in treating syphilis have been performed for the period of 25 years. It was found that, introduction of the Bulletin of the Russian Ministry of Health No. 2516/3199 95-27 as of 01.12.95 into the clinical practice that permitted treatment of early syphilis forms (including treatment of pregnant females) with benzathine benzylpenicillin was accompanied by an abrupt increase in the number of individuals lacking the negative reaction of non-treponemal tests (NTTs). There are more cases of clinical and serological relapses, congenital syphilis, and neurosyphilis, mainly in patients with secondary and especially with latent early syphilis who were treated by benzathine benzylpenicillin. The reservoir of neurosyphilis has been demonstrated to be individuals lacking the negative reaction to NTT. Pharmacokinetic studies of penicillins in blood serum and in the amniotic and cerebrospinal fluids conducted by the authors have revealed an insufficient minimum inhibitory penicillin concentration against Treponema pallidum upon administration of benzathine benzylpenicillin, and the latter has been recommended for exclusion from treatment settings for latent early syphilis and secondary syphilis with the disease duration of more than 6 months. The problem of syphilis has been emphasized to be topical at present due to a large proportion of latent forms of the disease, serological resistance, and neurosyphilis.