Irritant contact dermatitis (ICD) is a non-allergic local inflammatory reaction of a skin and one of the most frequent occupational health problems. Silymarin has been clinically used in Europe for a long time to treat liver diseases and also known to have anti-cancer and anti-inflammatory activities. In the present study, we report that topical application of silymarin reduces chemical-induced ICD. Topical application of 2,4-dinitrochlorobenzene (DNCB) induced an ear swelling in BALB/c mice and silymarin suppressed DNCB-induced increase in ear thickness. Prophylactic and therapeutic application of silymarin showed similar effect on DNCB-induced increase in ear thickness and skin water content. In addition, phobor ester- or croton oil-induced increase in ear thickness was also inhibited by silymarin treatment. Silymarin also blocked neutrophil accumulation into the ear induced by these irritants. Further study demonstrated that DNCB-induced tumor necrosis factor-alpha (TNF-alpha) expression in mouse ear was suppressed by silymarin. DNCB-induced expression of KC, one of the main attractors of neutrophil in mice, and adhesion molecules, including intercellular adhesion molecule-1 (ICAM-1) and E-selectin in mouse ear were also inhibited by silymarin. Moreover, TNF-alpha-induced expression of cytokines, such as TNF-alpha and IL-1beta, and a chemokine, IL-8, were suppressed by silymarin treatment in human keratinocyte cell line, HaCaT. Silymarin also blocked TNF-alpha- and DNCB-induced NF-kappaB activation in HaCaT. Collectively, these results demonstrate that topically applied silymarin inhibits chemical-induced ICD in mice and this might be mediated, at least in part, by blocking NF-kappaB activation and consequently inhibiting the expression of cytokines and adhesion molecules.