ABSTRACT: INTRODUCTION: Insulin resistance (IR), a risk factor for the development of cardiovascular disease, is common among patients with Rheumatoid Arthritis (RA). Inflammation, and especially tumour necrosis factor alpha (TNFalpha), has been associated with IR, and the administration of anti-TNFalpha agents is suggested to improve insulin sensitivity. However the effects of obesity, a potent contributor to IR, to this improvement have not been studied in RA. The aim of this study is to compare the effects of anti-TNFalpha therapy on IR between normal-weight and obese patients with RA. METHODS: Patients who were normal-weight with IR (N+IR) or obese with IR (O+IR), and embarked on anti-TNFalpha treatment participated. Assessments included body mass index (BMI), insulin sensitivity (Homeostasis Model Assessment of insulin resistance, HOMA and the Quantitative Insulin sensitivity Check Index, QUICKI), RA disease characteristics before and following 6 months of anti-TNFalpha treatment. Their results were compared to matched (for age, gender, BMI, disease duration and smoking status) normal-weight patients without IR (N-IR) and obese without IR (N-IR) respectively. In total, 32 patients were assessed for this study, with 8 in each group. RESULTS: Following 6 months of treatment, disease activity was significantly reduced in all groups (P<0.05) to a similar extent (P for differences between groups >0.05 in all cases). In the total population, changes in HOMA (mean reduction at 6m = -0.2 +/-0.1; P=0.088) and QUICKI (mean increase at 6m = 0.03 +/-0.022; P=0.092) after treatment were not statistically significant, though a trend towards improvement was observed. However, N+IR patients showed a significant decrease in HOMA (mean reduction at 6m = -0.54+/-0.2; P=0.002) and increase in QUICKI (mean increase at 6m = 0.046+/-0.02; P=0.011). These changes were significantly different compared to the other groups (P<0.05 in all cases). Multivariable analyses showed that the change in Erythrocyte Sedimentation Rate (ESR), and the change in C-Reactive Protein (CRP) associated with the improvement in HOMA (ESR: F1-7= 5.143, P=0.019; CRP: F1-7= 3.122, P=0.022) and QUICKI (ESR: F1-7= 3.814, P=0.021; CRP: F1-7= 2.67; P=0.041) only in the N+IR group. CONCLUSIONS: Anti-TNFalpha therapy, through controlling inflammation, seems to improve insulin sensitivity in normal-weight RA patients with insulin resistance, but is not sufficient to achieve the same beneficial effect in obese RA patients with insulin resistance.