Aim To analyze the effect of vitamin D administration on serum 25-hydroxyvitamin D (25[OH]D) level and biomarkers of metabolic syndrome and atherosclerosis: homeostatic model assessment of insulin resistance (HOMA-IR), adiponectin, homocysteine, and high sensitivity C-reactive protein (hs-CRP) in epilepsy patients receiving enzymatic antiseizure medications (ASMs). Methods This double-blind, randomized, placebo-controlled trial included 40 adult epilepsy patients treated with enzymatic ASMs to receive vitamin D3 (2,000 IU/day) or placebo for 12 weeks. The primary outcome was a change in serum 25(OH)D level. Secondary outcome included changes in HOMA-IR, adiponectin, homocysteine, and hs-CRP. Data were analysed using a per-protocol approach. Results Thirty-four patients completed the study. Vitamin D supplementation yielded a significantly greater increase in serum 25(OH)D (10.67±8.16 vs. –1.29±3.96 ng/mL; p<0.001) and adiponectin (1.38±3.05 vs. 0.34±1.89 µg/mL; p=0.045), as well as a significantly greater reduction in hs-CRP (–6.74±14.65 vs. 1.81±7.75 mg/L; p=0.041) compared with placebo. Conversely, no significant differences were observed between groups regarding the changes in HOMA-IR (–0.24±3.71 vs. –0.14±3.38; p=0.940) or homocysteine (7.90±1.79 vs. 8.15±2.70 µmol/L; p=0.290). Conclusion Vitamin D supplementation (2,000 IU/day) effectively restores 25(OH)D level and improves adiponectin and hs-CRP in epilepsy patients on enzymatic ASMs, suggesting a potential benefit for cardiovascular risk reduction. However, vitamin D alone did not prevent the rise in homocysteine, likely due to the concurrent cessation of B-vitamin supplementation. © 2026, Medical Association of Zenica-Doboj Canton. All rights reserved.