BACKGROUND AND PURPOSE: It is thought that the anti-inflammatory effects of glucocorticoids (GCs) are largely due to GC receptor (GR)-mediated transrepression of NF-κB and other transcription factors, whereas side effects are caused by activation of gene expression (transactivation). Selective GR modulators (SGRMs) that preferentially promote transrepression should retain anti-inflammatory properties whilst causing fewer side effects. Contradicting this model, we found that anti-inflammatory effects of the classical GC dexamethasone were partly dependent on transactivation of the dual specificity phosphatase 1 (DUSP1) gene. We wished to determine whether anti-inflammatory effects of SGRMs are also mediated by DUSP1. EXPERIMENTAL APPROACH: Dissociated properties of two SGRMs were confirmed using GR- and NF-κB-dependent reporters, and capacity to activate GC-responsive elements of the DUSP1 gene was tested. Effects of SGRMs on the expression of DUSP1 and pro-inflammatory gene products were assessed in various cell lines and in primary murine Dusp1(+/+) and Dusp1(-/-) macrophages. KEY RESULTS: The SGRMs were able to up-regulate DUSP1 in several cell types, and this response correlated with the ability of the compounds to suppress COX-2 expression. Several anti-inflammatory effects of SGRMs were ablated or significantly impaired in Dusp1(-/-) macrophages. CONCLUSIONS AND IMPLICATIONS: Like dexamethasone, SGRMs appear to exert anti-inflammatory effects partly via the up-regulation of DUSP1. This finding has implications for how potentially therapeutic novel GR ligands are identified and assessed.