Chronic inflammation is a major etiology of cancer. Accumulating epidemiological and experimental evidences suggest that intake of high protein diet (HPD) is associated with colitis-associated colon cancer, however, most of the studies were confined in colon. Systemic influence of HPD on inflammation indices in different tissues of an organism has never been studied. We therefore investigated the effect of HPD on mouse skin and colonic inflammation using the well characterized inflammation induction protocol in both tissues (12- O -tetradecanoylphorbol-13-acetate [TPA] for skin and dextran sodium sulfate [DSS] for colon). ICR mice were grouped to normal diet (ND, 20% casein) or HPD (50% casein) groups. In each diet group, mice were treated with either vehicle (acetone or H₂O), TPA, TPA and DSS, or DSS. Experimental diet was fed for total 4 weeks. After 1 week of diet feeding, 6.5 nmol of TPA was topically applied twice a week for 2 weeks on the shaved mouse dorsal skin. Drinking water containing 2% DSS was administered for 7 days at the final week of experiment. The results showed that TPA-induced skin hyperplasia, epidermal cell proliferation, and cyclooxygenase-2 (COX-2) expression were reduced in HPD group compared to ND group. In contrast, HPD increased DSS-induced colon mucosal hyperplasia, colonocyte proliferation, COX-2 expression, and plasma nitric oxide compared to ND group. This suggests that HPD exerts differential effect on different tissue inflammation which implies efficacy of protein intervention to human also should be monitored more thoroughly.