The active metabolite of vitamin D calcitriol and its analogs are well‐known for their anti‐inflammatory action in the skin, while their main side effect associated with topical treatment of inflammatory disorders is irritant contact dermatitis. Prostaglandin E2 (PGE2) is pro‐inflammatory at the onset of inflammation and anti‐inflammatory at its resolution. We hypothesized that induction of PGE2 synthesis by calcitriol in epidermal keratinocytes may contribute both to its pro‐inflammatory and anti‐inflammatory effects on the skin. Treatment of human immortalized HaCaT keratinocytes with calcitriol (3–100 nM, 2–24 h) increased PGE2 production due to increased mRNA and protein expression of COX‐2, but not to increase of COX‐1 or release of arachidonic acid. The effect of calcitriol on COX‐2 mRNA was observed also in primary human keratinocytes. The increase in COX‐2 mRNA is associated with COX‐2 transcript stabilization. Calcitriol exerts this effect by a rapid (2 h) and protein synthesis independent mode of action that is dependent on PKC and Src kinase activities. Treatment with a COX‐2 inhibitor partially prevented the attenuation of the keratinocyte inflammatory response by calcitriol. We conclude that upregulation of COX‐2 expression with the consequent increase in PGE2 synthesis may be one of the mechanisms explaining the Janus face of calcitriol as both a promoter and attenuator of cutaneous inflammation. J. Cell. Physiol. 9999: 1–7, 2015. © 2015 Wiley Periodicals, Inc.