The biological activity of the pro‐inflammatory cytokine, tumor necrosis factor (TNF)‐α depends on the level of TNF‐α itself, the expression of the p55 and p75 cell surface receptors for TNF on target cells and the concentrations of the natural inhibitors of TNF‐α, the soluble p55 and p75 TNF receptors (TNF‐R). Interleukin (IL)‐10 and IL‐4 are known to inhibit TNF‐α production by monocytes. We, therefore, investigated the effects of IL‐10 and IL‐4 on the cell surface expression and release of TNF‐R by human monocytes to determine whether these cytokines also indirectly modulated the biological activity of TNF‐α. Exposure to IL‐10 (1‐10 U/ml) for 24 or 48 h increased soluble p75 TNF‐R expression and concomitantly reduced surface expression of p75 TNF‐R. Further, IL‐l α‐stimulated production of TNF‐α was diminished by IL‐10 and only a small proportion of this TNF‐α was bioactive, consistent with increased production of inhibitory soluble TNF‐R. IL‐10 also induced down‐regulation of surface p55 TNF‐R on monocytes, and increased release of soluble p55 TNF‐R. However, the expression of soluble p55 TNF‐R was much lower than soluble p75 TNF‐R, indicating that it contributed less importantly to neutralization of TNF‐α under these conditions. Like IL‐10, IL‐4 supressed the release of TNF‐α by monocytes. In contrast to IL‐10, however, IL‐4 (0.1‐10 ng/ml) supressed the release of soluble p75 TNF‐R from monocytes in a dose‐dependent manner. Release of soluble p55 TNF‐R was also supressed by IL‐4. IL‐10, therefore, reduces the pro‐inflammatory potential of TNF in three ways: by down‐regulating surface TNF‐R expression whilst increasing production of soluble TNF‐R and inhibiting the release of TNF‐α itself. This suggests that IL‐10 may be useful in the treatment of diseases where overexpression of TNF‐α occurs.