Dual specificity phosphatase DUSP1 (otherwise known as mitogen-activated phosphatase 1 or MKP-1) dephosphorylates MAP kinases particularly p38 and negatively regulates innate immunity. Recent studies have shown that the DUSP1 gene is transcriptionally upregulated by glucocorticoids (GCs) and that the antiinflammatory action of GCs is impaired in DUSP1-/- mice. Here we show that GC-mediated dephosphorylation of ERK-1 and ERK-2 activated by IgE receptor cross-linking is unimpaired in bone marrow-derived mast cells (BMMC) of DUSP1-/- mice. Dephosphorylation of phospho-p38 MAPK is impaired but only at early times of GC treatment. Proinflammatory cytokine and chemokine gene expression (CCL2, IL-6, TNF) is still downregulated by GCs in BMMC from DUSP1-/- mice suggesting a compensatory mechanism for the GC action in these mice. In both DUSP1+/+ and DUSP1-/- BMMC, GC upregulated the expression of several phosphatase genes (DUSP2, DUSP4, DUSP9 and PEST domain-enriched tyrosine phosphatase). DUSP1-/- mice show enhanced mast cell degranulation and are highly susceptible to anaphylaxis but these effects are still downregulated by GCs. GCs also repressed other inflammatory responses such as dinitrofluorobenzene-induced contact hypersensitivity and lipopolysaccharide-induced mortality in DUSP1-/- mice. Thus GC-mediated antiinflammatory action is largely independent of DUSP1.