Ligands for the receptor for advanced glycation endproducts (RAGE) are increased in RA synovial fluid (SF), serum and synovium. Since RAGE is present on fibroblast-like synoviocytes (FLS), the present study investigates whether the RAGE ligands HMGB-1 and AGEs are able to stimulate the characteristic, pathological invasive behaviour of these cells. FLS were obtained during joint replacement surgery. FLS were seeded in serum free medium with HMGB-1 or glycated albumin (BSA-AGE) on transwell filters coated with Matrigel. The lower compartment contained medium with serum as a chemoattractant. After three days, the percentage of invading cells was determined and compared to the control invasion. Stimulation with HMGB-1 increased invasiveness to 125% compared to the control (p = 0.001). Addition of anti-RAGE antibody reduced this back to baseline (98%, p = 0.002). Stimulation with BSA-AGE, another RAGE ligand, increased invasiveness to 150% compared to the control (p = 0.003). Addition of anti RAGE was again able to reduce the increased invasiveness back to baseline (95%, p = 0.008). HMGB-1 and BSA-AGE stimulated the invasiveness of RA-FLS by activation of RAGE. As such, RAGE may be an interesting target for therapy directed at the inhibition of synoviocyte activation. © Copyright Clinical and Experimental Rheumatology 2007.