Exchange protein directly activated by cAMP (EPAC) mediates protein kinase A (PKA)-independent cAMP signalling pathways. We recently showed that EPAC is responsible for cAMP-mediated induction of suppressor of cytokine signalling-3 (SOCS3) in human umbilical vein endothelial cells (HUVECs)(1). Using an EPAC-selective cAMP analogue (8-pCPT-2’-O-Me-cAMP) and siRNA knockdown of EPAC1, we have demonstrated that cAMP-mediated induction of SOCS3 in murine embryonic fibroblasts (MEFs) is also EPAC-dependent. MEFs null for CCAAT/enhancer binding proteins (C/EBPs) β or δ did not show increased expression of SOCS3 in response to EPAC activation; additionally, electrophoretic mobility shift assays and functional chromatin immunoprecipitation assays showed both an increase in C/EBP binding activity to consensus binding sites, and specific binding of C/EBPs to the SOCS3 promoter when HUVECs were treated with forskolin or 8-pCPT-2’-O-Me-cAMP. Transient overexpression of C/EBPs in HUVECs increased SOCS3 induction after EPAC activation, while antisense knock-down had the opposite effect. These data demonstrate that EPAC mediates cAMP-induced SOCS3 induction through the C/EBP family of transcription factors, and this represents a previously unrecognised mode of cAMP-controlled gene expression.