In a recent study from our group, the combination of methotrexate and sulphasalazine (MTX + SASP) seemed superior to MTX alone in the treatment of rheumatoid arthritis (RA). To assess the impact of these therapies on the cytokine cascade, the in vitro production and circulating concentrations of several cytokines and endogenous cytokine antagonists were measured in 30 healthy controls and longitudinally in a subset of 26 patients enrolled in this study. Compared to controls, RA patients had significantly higher circulating concentrations of interleukin-6 (IL-6), soluble receptors for tumour necrosis factor (sTNFR), soluble receptors for interleukin-2 (sIL-2R) and interleukin-1 receptor antagonists (IL-1RA), and their peripheral blood mononuclear cells (PBMNC) showed a higher spontaneous production of interleukin-1 beta (IL-1 beta), tumour necrosis factor alpha (TNF alpha) and IL-1RA (both secreted and cell-associated) and a higher stimulated production of cell-associated TNF alpha, IL-1RA and (to a lesser extent) IL-1 beta. Treatment with MTX alone (n = 12) or combined with SASP (n = 14), resulted in significant reductions of circulating IL-6 and sIL-2R but did not alter IL-1 beta, TNF alpha or IL-1RA concentrations. Decreases in circulating levels of sTNFR and in the in vitro production of cell-associated IL-1 beta and IL-1RA after stimulation were only observed in patients treated with MTX + SASP. The concentrations of IL-1RA and sTNFR in the circulation exceeded moderately those of IL-1 beta and TNF alpha but this is probably insufficient to block IL-1 and TNF alpha activity. In conclusion, therapy with MTX alone or with SASP modulates IL-6 and sIL-2R concentrations in RA. Decreased production of IL-1 beta and IL-1RA and circulating sTNFR levels were only observed during therapy with MTX + SASP. Whether this relates to the better clinical effect observed with the combination therapy remains to be investigated. Circulating levels of IL-6, sIL-2R and sTNFR seem useful markers of disease activity in RA.