Ligation of Toll‐like receptors (TLR) on macrophages induces cytokines and mediators important for the control of pathogens. Macrophage activation has to be tightly controlled to prevent hyper‐inflammation. Accordingly, the hallmarks of TLR‐triggered signaling, nuclear translocation of NF‐κB and phosphorylation of mitogen‐activated protein kinases (MAPK), are transient events. We have mined microarray datasets for changes in the expression of phosphatases in resting and TLR‐activated macrophages. Several members of the dual‐specificity phosphatases (DUSP) were induced upon triggering TLR4 with LPS. Up‐regulation of DUSP1 mRNA was transient after stimulation with LPS alone, but addition of the immunosuppressive cytokine IL‐10 resulted in robust, continued DUSP1 expression. IL‐10 also synergized with the anti‐inflammatory glucocorticoid dexamethasone in the induction of DUSP1 mRNA expression in activated macrophages, as well as in the inhibition of IL‐6 and IL‐12 production. Increased expression of DUSP1 in IL‐10‐treated activated macrophages was correlated with a faster down‐regulation of p38 MAPK activation. Thus, these data suggest an operational link between IL‐10 and inibition of p38 MAPK via sustained expression of DUSP1.