The B-cell-activating factor (BAFF), a member of the tumor necrosis factor (TNF) family, has recently attracted attention as a potent cytokine, involved in B-cell stimulation and survival of autoimmune cells. Despite its significance in the pathogenesis of autoimmune diseases, data is limited and inconclusive regarding its expression in different stages of rheumatoid arthritis (RA). The aim of this study was to assess BAFF in biologic-naïve RA patients with early versus established disease and monitor its levels in response to anti-TNF treatment in seronegative- and seropositive patients. Based on our results, B-cell-activating factor (BAFF) did not appear to be overexpressed or differentially expressed early (≤2 years duration) in comparison to established rheumatoid arthritis (RA). Moreover, tumor necrosis factor (TNF) blockade did not appear to affect BAFF levels in either seropositive or seronegative RA patients, despite the association of anti-TNF treatment with the development of autoantibodies and the known anti-apoptotic effects of BAFF. As expected, BAFF became induced after B-cell depletion. Investigation of the effect of different biologics on the expression of BAFF and other cytokines will help elucidate the interconnecting immune pathways involved in the initiation and perpetuation of the inflammatory process.