The wide range of manifestations of systemic lupus erythematosus (SLE) contributes to a reduction in the quality and duration of life of the patients. The high incidence of the disease among the young population leads to an increase in both direct and indirect costs to the state for this group of patients. Achieving remission and reducing damage from the disease is only possible with the right treatment, often involving the use of expensive biologics. However, the comparative clinical and economic efficacy of these therapies remains inadequately explored. Objective: To evaluate the comparative clinical-economic effectiveness of 12-month therapy with belimumab (BLM), anifrolumab (AFL), and rituximab (RTX) in patients with active SLE. Materials and methods. Sixty-eight patients with moderate-to-high SLE activity were enrolled in the study. Patients were newly initiated on biologics therapy: 29 pts received BLM (Group 1), 22 pts received AFL (Group 2), and 17 pts received RTX (Group 3) for a 12-month period. Treatment response was defined as a reduction in SLE activity according to SLEDAI-2K, achieving low activity (SLEDAI-2K ≤ 4) or remission (SLEDAI-2K = 0). Pharmacoeconomic analysis employed a Cost-Effectiveness Analysis (CEA) by calculating the Cost-Effectiveness Ratio (CER) using the Cost Per Responder (CPR) model. Results and discussion. After six months of biologics therapy, patients exhibited a significant decline in SLE activity by SLEDAI-2K. Low activity/remission was attained by 62% of patients in the BLM group, 77% in the AFL group, and 12% in the RTX group. By the 12-month mark, the proportion of responders continued to increase, reaching 79% in Group 1, 91% in Group 2, and 41% in Group 3. The CER at six months was lowest in the AFL group (415,000 RUB), compared to 445,000 RUB in the BLM group and over 1 million RUB in the RTX group. At 12 months, CER values in Groups 1 and 3 were nearly equivalent at approximately 630,000 RUB, while Group 2 reached 702,000 RUB. TheIncremental Cost-Effectiveness Ratio (ICER) at six months was similar across comparisons (BLM vs. AFL, AFL vs. RTX, and BLM vs. RTX), approximating 290,000 RUB. At 12 months, ICER values were 1.2 million RUB for AFL vs. BLM, 757,000 RUB for AFL vs. RTX, and 624,000 RUB for BLM vs. RTX. Conclusion. The six-month therapy with AFL demonstrated superior clinical efficacy and economic affordability compared to BLM and RTX. However, the clinical-economic benefits of AFL diminished by the end of the 12-month treatment period, underscoring the need for a comprehensive assessment of short- and long-term economic factors when selecting optimal SLE treatment strategies.