Abstract: Cardiovascular morbidity and mortality appear to be increased in rheumatoid arthritis (RA), which might be due to increased prevalence of risk factors for cardiovascular disease, such as an accelerated progression of atherosclerosis. Patients with active RA frequently show an atherogenic lipid profile, which has been linked with the inflammatory reaction. Tumor necrosis factor-α (TNF-α), a pivotal proinflammatory cytokine implicated in the pathogenesis of atherosclerosis in RA, may be involved in the development of the altered lipid profile observed in active RA. Our aim was to investigate the effects of anti-TNF-α treatment in combination with methotrexate (MTX) and corticosteroid therapy on lipid profile in patients with active RA. In this prospective study 34 consecutive RA patients were included (all women, mean age 51.6 ± 7.9 years, range 46–72 years) with active (defined as Disease Activity Index 28 joint score [DAS-28], of at least 3.2) and refractory RA, in stable treatment with MTX (7.5–10 mg/week) and prednisone (7.5–10 mg/day) for 3 months. All patients received TNF-α blockers (n= 16, etanercept 25 mg twice weekly; n= 14, infliximab 3 mg/kg on 0, 2, 6, and every 8 weeks thereafter; and finally, n= 4, adalimumab 40 mg every other week). Total cholesterol, high-density lipoprotein cholesterol (HDL cholesterol), triglycerides (TG) and lipoprotein (a) [Lp(a)] levels and the atherogenic index (ratio cholesterol/HDL cholesterol) were measured at base line, and at 16 and 24 weeks. Results were as follows: The DAS-28 was 6.9 ± 2.1 at base line and decreased to 4.6 ± 1.8 after 16 weeks, and further to 4.1 ± 1.3 after 24 weeks (both, P < 0.01). Following anti-TNF-α treatment, the mean levels of total cholesterol were 168 ± 24 mg/dL at base line and increased to 188 ± 28 mg/dL at 16 weeks (P < 0.01), and 197 ± 26 mg/dL at 24 weeks (P < 0.001). However, also the mean levels of HDL cholesterol were significantly higher than basal values after 16 and 24 weeks of treatment (34 ± 12 mg/dL versus 36 ± 18 mg/dL [P < 0.05] and 38 ± 14 mg/dL [P < 0.01], respectively). TG and Lp(a) levels, as well as the atherogenic index were not significantly changed. Interestingly, variations in disease activity were significantly and inversely correlated with HDL cholesterol levels. In conclusion: Short anti-TNF-α treatment was associated with a significant increase of both total cholesterol and HDL cholesterol levels, and correlated with decreased disease activity. The atherogenic index showed no changes during the study. Therefore, anti-TNF-α treatment might affect lipid profile in RA patients.