Recent reports have suggested that PKCε contributes to systemic insulin resistance, and is involved in the pathogenesis of type 2 diabetes, however, the exact mechanism is still unknown. To elucidate the possible involvement of PKCε in the pathogenesis of type 2 diabetes, we examined the role of PKCε in differentiated adipocytes using mouse 3T3-L1 adipocytes. We found that the over-expression of PKCε resulted in the increase of IL-6 expression in differentiated adipocytes. This PKCε-induced IL-6 expression could be completely inhibited by U0126, an inhibitor of mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase. We also demonstrated that PKCε increased the transcriptional activity of Est-like transcription factor (Elk-1) as well as the DNA-binding activity of activator protein-1 (AP-1) in differentiated 3T3-L1 adipocytes. These results suggest that PKCε is able to increase IL-6 expression via the ERK–AP-1 pathway in differentiated adipocytes, and that PKCε is involved in systemic insulin resistance by regulating plasma IL-6 concentrations.