BACKGROUND: Despite the high efficacy of targeted therapy in psoriasis, there is an increase in loss of response (escape phenomenon), including due to the formation of antibodies against biologicals. At the same time, the role of other factors is insufficiently studied. These include comorbidities that are common in psoriasis, such as gastrointestinal diseases, bacterial endotoxemia, and intestinal or skin microbiocenosis disorders. AIM: The work aimed to assess the effect of netakimab, an IL-17A inhibitor, on the long-term efficacy of psoriasis therapy by targeting bacterial endotoxemia and abnormal intestinal and skin microbiocenosis. METHODS: The study included 30 patients with severe plaque psoriasis who received netakimab, an IL-17A inhibitor, between 2021 and 2024. The Psoriasis Area and Severity Index (PASI) was measured at baseline and weeks 12, 28, and 52 to assess treatment efficacy (PASI 75/90/100). At weeks 28 and 52, bacterial endotoxin levels in peripheral blood were measured, and intestinal and skin microbiota parameters were assessed using chromatography–mass spectrometry. In patients with a relapse (escape phenomenon) and abnormal markers of bacterial endotoxin and intestinal and skin microbiota, treatment was prescribed to improve microbiocenosis, and its impact on the efficacy of targeted therapy was assessed. RESULTS: At baseline, the mean PASI, Dermatology Life Quality Index, and endotoxin level were 38.4 ± 2.7, 29.3 ± 3.5, and 2.7 ± 0.35 nmol/mL, respectively. By week 52, the majority of patients (24; 80%) reached PASI 90/100. At week 28, 6 (20%) patients had a loss of response with persistent endotoxemia (2.5 ± 0.4 nmol/mL) and signs of dysbiosis. Following treatment to improve microbiocenosis, the endotoxin level decreased to 0.5 ± 0.1 nmol/mL, resulting in clinical remission with PASI 90 by week 52. By week 104, 70% of patients remained in remission (PASI 90/100), and 30% had PASI 75. CONCLUSION: Persistent endotoxemia and dysbiosis were associated with the escape phenomenon on netakimab therapy; the treatment restored the response to PASI 90 and provided sustained remission. To maintain netakimab’s long-term efficacy, it is advisable to re-evaluate endotoxemia and microbiota by chromatography–mass spectrometry at weeks 28 and 52, and initiate treatment as needed.