We present a clinical observation of the failure of treatment of a patient with urethritis caused by M. genitalium (MG). Therapy with doxycycline was prescribed to the patient. However, complaints persisted at the follow-up visit. Control examination by real-time PCR showed the presence of MG in the urethra. After the course of treatment with azithromycin, complaints remained, MG was again detected in the urethra. A sample of the patient’s biological material was transferred to the laboratory of molecular diagnostics of the Research Institute of Antimicrobial Chemotherapy of the Smolensk State Medical University, where a nucleotide substitution at the A2059G position of the 23S rRNA gene in MG, indicating resistance of the microorganism to macrolides, was found. Therapy was adjusted by prescribing Moxifloxacin. Clinical and microbiological cure occurred after the end of therapy. The feature of this clinical case is that in the practice of dermatovenereologists, there may be cases of ineffectiveness of treatment of MG infection with tetracyclines (doxycycline) and macrolides (azithromycin), which requires a change in therapy tactics. The optimal approach includes pre-test of patients’ biological samples for MG antimicrobial resistance mutations and personalization of therapy according to the antibiotic resistance profile.