Interleukin (IL)‐21 and IL‐15 belong to the common γ‐chain receptor family. IL‐15 represents a novel therapeutic target in rheumatoid arthritis (RA), whereas less is known about the role of IL‐21 in human inflammatory diseases. We have analysed the effects of blocking IL‐21 and IL‐15 on spontaneous production of pro‐inflammatory cytokines in RA synovial cell cultures. RA synovial membrane cells were cultured in the presence of an IL‐21R‐Fc chimera or a neutralizing IL‐15 antibody and production of tumour necrosis factor (TNF)α, IL‐6 and IL‐1β was measured by enzyme‐linked immunosorbent assay (ELISA). Expression of IL‐21 and IL‐15 in RA synovium was measured by RT‐PCR and ELISA. mRNA for IL‐21 and IL‐21R was detected in the culture cell lysates. Protein for IL‐15 was found at detectable levels in the cell lysates. Both the IL‐21R‐Fc chimera and anti‐IL‐15 antibody inhibited cytokine release, although substantially more IL‐21R‐Fc was needed. IL‐21R‐Fc at the highest dose (100 μg/ml) significantly reduced TNFα production by 50%, IL‐6 by 57% and IL‐1β by 81%. Anti‐IL‐15 antibody (5 μg/ml) significantly inhibited TNFα release by 51%, IL‐6 by 37% and IL‐1β by 82% in line with previous published observations. The data confirm that IL‐15 plays a role in RA and suggests that IL‐21 is also involved in driving the pro‐inflammatory cytokine response in RA.