Rheumatoid arthritis (RA) is a systemic autoimmune disease driven by highly active autoantibody producing B cells. These B cells can be supported within ectopic germinal centers found in afflicted joints. Fibroblast like synoviocytes (FLS) present in inflamed joints support B cell survival, activation and differentiation. CD27 ⁺ memory B cells and naïve B cells show very distinct reactions to activation, particularly by CD40 ligand (CD40L). We show that FLS dependent activation of human B cells is dependent on interleukin 6 (IL-6) and CD40L. FLS have been shown to activate naïve as well as memory B cells. If the activatory potential of FLS is different for naïve and memory B cells had not yet been investigated. Our results suggest that FLS-induced activation of B cells is dependent on IL-6 and CD40L. While FLS are capable of inducing differentiation, isotype switching and antibody production in memory B cells, FLS capability to activate naive B cells is significantly lower.