Anti-CD4 MoAbs have been successfully used in initial treatment trials of rheumatoid arthritis. One remarkable feature of this therapy was the early reduction of synovitis along with a decrease of the erythrocyte sedimentation rate (ESR) and the C-reactive protein (CRP). Since not only T helper cells, but also monocytes-macrophages bear the CD4 antigen, the question was raised whether the immediate effects observed may have been in part due to an influence on the mononuclear phagocyte system. Immediately after MoAb infusions, a significant reduction of the absolute peripheral blood monocyte count down to 30% (P < 0.001) was noted within the first hour of injection. In contrast to strikingly elevated levels of soluble CD4 after treatment which was indicative of T cell lysis, soluble CD14 levels did not rise, but rather decreased from previously elevated levels. Before treatment, activation of the monocyte-macrophage system had been signified by elevated serum levels of IL-1, IL-6, CRP and neopterin as well as a marked in vitro production of IL-1, tumour necrosis factor-alpha (TNF-alpha) and IL-6. Subsequent anti-CD4 treatment resulted in a rapid and significant reduction of monocyte-derived circulating cytokines and mediators concordant with a reduced capacity to produce IL-1, TNF-alpha, and IL-6 in those patients who demonstrated clinical benefits. Therefore, studies of monocyte activation markers may be useful in identifying subsequent responders to anti-CD4 therapy.