OBJECTIVE: The aim of the present study was to investigate the associations of cumulative inflammatory burden (assessed by serial measurements of inflammatory markers) and classical cardiovascular disease (CVD) risk factors with asymmetric dimethylarginine (ADMA) in a large prospective cohort of patients with established RA. METHODS: Two hundred and one RA patients [155 females, median age 67 years (range 59-73)] were assessed at baseline (2006) for the presence of classical CVD risk factors and determination of systemic inflammation by CRP and ESR. Global CVD risk was identified by the Framingham Risk Score and the Reynolds Risk Score. At follow-up (2012), ADMA levels were measured by ELISA. A quarterly measurement of CRP and ESR for each year the patient was in the study was used to produce an average area under the curve (AAUC) for ESR and CRP. RESULTS: Regression analysis revealed that baseline ESR in 2006 and the AAUC of ESR and CRP all had significant positive relationships with current ADMA (P = 0.004, P <0.001 and P = 0.002, respectively). Baseline CRP in 2006 was not a significant predictor of ADMA (P = 0.093), although this relationship was in the same direction as the other factors. These results remained consistent after adjustment for classical CVD risk factors. CONCLUSION: Cumulative inflammatory burden is positively associated with ADMA levels, suggesting a potential pathogenic mechanism through which chronic systemic inflammation exerts deleterious effects on nitric oxide metabolism and endothelial homeostasis. This association is independent of classical CVD risk factors.