Objective: Chronic inflammation in rheumatoid arthritis (RA) is associated with vascular endothelial dysfunction. The aim of this study was to determine the effect of spironolactone on endothelial function in anti-tumour necrosis factor (TNF)-naive RA patients. Methods: Twenty-four anti-TNF-naive RA patients (mean age 49±1.8 years; disease duration 8.5±5.8 years) with high disease activity [Disease Activity Score including a 28-joint count (DAS28>5.1)] despite treatment with stable doses of conventional disease-modifying anti-rheumatic drugs (DMARDs) were investigated. Inflammatory disease activity [DAS28 and Health Assessment Questionnaire-Disability Index (HAQ-DI) scores, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP)], serum markers of endothelial dysfunction, serum nitrite concentration, and endothelium-dependent and -independent vasodilation of the brachial artery were measured before and after 12 weeks of therapy with oral spironolactone 2 mg/kg/day. Results: After treatment with spironolactone, flow-mediated vasodilation (FMD) improved from 3.18±0.46% to 3.95±0.49% (p<0.001) whereas there was no significant change in endothelium-independent vasodilation with nitroglycerin and baseline diameter (18.4±1.15% vs. 18.3±1.13%, p = 0.046, and 3.5±0.1 vs. 3.52±0.1 mm, p = 0.952, respectively); serum nitrite concentration was reduced significantly from 6.9±0.34 to 6.8±0.33 µmol/L (p<0.001), ESR from 59.90±4.86 to 51.22±4.26 mm in the first hour (p<0.001), and CRP level from 15.2±3.8 to 9.4±2.6 mg/dL (p = 0.019). DAS28 and HAQ-DI scores were significantly reduced, from 6.9±0.25 to 4.1±0.31 (p<0.05) and from 1.47±0.09 to 0.69±0.1 (p<0.05), respectively. Conclusions: The study suggests that, in RA, endothelial dysfunction is part of the disease process and treatment with spironolactone improves both endothelial dysfunction and inflammatory disease activity in RA. [ABSTRACT FROM AUTHOR]