Introduction and Objectives: High-density lipoprotein cholesterol (HDL-C) is known to be a key player in reverse cholesterol transport and this function is associated with its atheroprotec-tive role. Low HDL-C is a strong independent risk factor for cardiovascular disease, premature atherosclerosis and increased oxidative stress. However, the clinical benefit of high HDL-C through diet or drug therapy is still controversial.Methods: This study included 50 patients with isolated low HDL-C (<= 35 mg/dl), 52 patients with isolated high HDL-C (>= 70 mg/dl), and 33 age-and gender-matched controls with normal HDL-C. 'Isolated' was defined as excluding all clinical conditions associated with increased oxidative stress and inflammation, which may affect the structural state of HDL-C. In addition to arylesterase (ARES) activity and plasma thiol levels, laboratory parameters associated with oxidative stress were also assessed.Results: Levels of ARES (758 [169-1150] vs. 945 [480-1215] and 821 U/l [266-1220]; p<0.01) and total thiols (233 +/- 41 vs. 259 +/- 46 mu mol/l; p=0.02) were markedly higher in patients with high HDL-C. More importantly, total antioxidant capacity, oxidative stress index, creatine and serum ARES levels were associated with changes in serum HDL-C levels.Conclusion: In patients with isolated high HDL-C, we determined that while serum ARES activity and plasma thiol concentrations were significantly higher, the other markers associated with oxidative stress decreased markedly. Additionally, the present study demonstrated that serum oxidative stress status is very important to maintain the positive effects of HDL-C.(c) 2022 Sociedade Portuguesa de Cardiologia. Published by Elsevier Espan tilde a, S.L.U. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).