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Objectives To evaluate the dynamics of C3, C4 and anti-dsDNA antibody levels and their association with clinical activity and flares in patients with systemic lupus erythematosus (SLE) treated with belimumab (BEL).Methods Retrospective longitudinal cohort study from the BELILES-GEAS registry. Serological markers were assessed at the time of SLE diagnosis, at baseline, at each follow-up visit (months 3, 6, 12, 18, and 24 after treatment initiation) and during disease flares.Results A total of 371 patients were included, with a median drug exposure of 13.2 months. At baseline, 70.1% of patients were seropositive. SLE Disease Activity Index 2000 (SLEDAI-2K) and cSLEDAI scores and prednisone doses decreased significantly over time, whereas serum C3 and C4 levels, anti-dsDNA positivity and immunosuppressant use remained stable. Among 95 (25.6%) patients who experienced 139 (14.5%) flares, longitudinal analysis adjusted by immunosuppressant use and prednisone dose revealed no association between flare occurrence and low C3 or C4, whereas anti-dsDNA antibody positivity was (C3 OR=1.31, 95% CI 0.82 to 2.09; C4 OR=1.08, 95% CI 0.62 to 1.86, and anti-dsDNA OR=1.81, 95% CI 1.09 to 3.01, respectively). When stratified by flare severity, low C3 levels showed a borderline association with moderate-to-severe flares (OR=1.82, 95% CI 0.99 to 3.31), while no significant associations were observed for C4 or for mild flares. There was no association between serum level of C3 or C4 and cSLEDAI. The flare-discriminative performance of SLEDAI-2K and cSLEDAI was similar (AUC-ROCs 0.779 vs 0.781, p=0.88).Conclusion In SLE patients treated with BEL, the clinical utility of serological markers appears dissociated from disease activity. While C3 and C4 levels were not clearly related to disease activity or flares, low C3 levels showed a borderline association with moderate-to-severe flares, and anti-dsDNA positivity remained associated with increased flare risk, supporting a clinical assessment–driven approach with complementary use of anti-dsDNA.