Abnormal upregulation of cyclooxygenase-2 (COX-2) has been frequently observed in various types of transformed and cancerous cells. Numerous anti-inflammatory agents have been shown to exert chemopreventive effects by targeting COX-2, a rate-limiting enzyme involved in the inflammatory process. Anthocyanins are naturally occurring polyphenolic compounds that endow various fruits, vegetables, and plants with intense colors. Peonidin is another representative anthocyanidin, but its chemopreventive potential has not been fully described. This article investigated the effect of peonidin on 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced COX-2 expression and transformation in JB6 P(+) mouse epidermal cells (JB6 P(+) cells). Treatment of JB6 P(+) cells with peonidin inhibited TPA-induced COX-2 expression, and also decreased TPA-induced neoplastic transformation and blocked TPA-induced phosphorylation of extracellular signal-regulated kinases (ERKs) in the cells. The inhibition of the signaling mechanism regulating the activation of ERKs strongly suggests that peonidin exhibits chemopreventive as well as anti-inflammatory activities.