Objective. To evaluate the impact of endovenous laser ablation (EVLA) combined with micronized purified flavonoid fraction (MPFF), sulodexide, and their combination on the dynamics of circulating biomarkers and quality of life in patients with varicose vein disease of the lower extremities. Material and methods. A prospective study included 173 patients who underwent EVLA. They were allocated into four groups: EVLA alone (n=44), EVLA+MPFF (n=43), EVLA+sulodexide (n=43), and EVLA+MPFF+sulodexide (n=43). MPFF was prescribed at 1000 mg/day and sulodexide at 500 LSU/day for two months. Serum levels of E-selectin, MCP-1, VEGF, MMP-2, and MMP-9 were measured using ELISA at baseline (V0), after 2 months (V2), and after 12 months (V3). Quality of life was assessed with validated questionnaires CIVIQ-20 and SF-36. Results. EVLA alone provided early improvements in quality of life and reductions in E-selectin and MCP-1, although the effect partially diminished by 12 months in patients with advanced disease. MPFF mainly reduced MCP-1 (213.8 → 115.5 pg/mL; p<0.001) and VEGF (109.6 → 52.6 pg/mL; p<0.001), particularly in patients with CEAP C2–C3. Sulodexide significantly decreased MMP-2 (517.8 → 250.8 ng/mL; p<0.001) and MMP-9 (19.4 → 9.9 ng/mL; p<0.001) in CEAP C4–C6, although the effect partly attenuated at 12 months. The most pronounced and sustained effect was observed in the combination group: E-selectin (60.1 → 43.1 ng/mL), MCP-1 (265.4 → 131.3 pg/mL), VEGF (188.7 → 87.1 pg/mL), MMP-2 (487.8 → 230.1 ng/mL), and MMP-9 (19.8 → 8.7 ng/mL) all significantly decreased (all p<0.001), while improvements in CIVIQ-20 and SF-36 were maintained throughout one year. Conclusion. EVLA provides clinical improvement and reductions in inflammatory biomarkers, but the effect is less durable in advanced disease. MPFF primarily modulates MCP-1 and VEGF, while sulodexide acts on MMP-2 and MMP-9. Their combination shows complementary pathogenetic mechanisms, yielding the most durable biochemical and clinical benefits, and may represent the optimal pharmacological support for EVLA in patients with severe chronic venous disease.