Epidermal cells produce cytokines as a part of the body’s response to various external stimuli. Though extracellular ATP-induced activation of P2 receptors is involved in cytokine production in epidermal cells, it is not known whether activation of P1 receptors by extracellular adenosine leads to IL-6 production in epidermal cells. Here, we show that activation of adenosine A2B receptor induces IL-6 production via phosphorylation of epidermal growth factor receptor (EGFR) in human keratinocyte HaCaT cells. We found that treatment of HaCaT cells with 100 μM adenosine or with A2B receptor-specific agonist BAY60-6583 induced IL-6 production, and the production of IL-6 was suppressed by pretreatment with A2B receptor-specific antagonist PSB603. Adenosine- induced IL-6 production was also suppressed by A2B receptor knockdown. In addition, adenosine- and BAY60-6583-induced IL-6 production was suppressed by treatment with EGFR antagonist AG1478. Furthermore, adenosine and BAY60-6583 induced EGFR phosphorylation, and this phosphorylation was suppressed by A2B receptor knockdown. Thus, our data indicate that the A2B receptor-EGFR pathway has a role in IL-6 production. This in turn suggests that extracellular adenosine is involved in skin inflammation.