This study was conducted to assess protective effect of an antioxidant protein, sericin, on tumor promotion in the 7,12-dimethylbenz (alpha) anthracene (DMBA)-initiated and 12-O-tetradecanoylphorbol 13-acetate (TPA)-promoted mouse skin tumorigenesis model. In experiment 1, sericin was applied topically to DMBA-initiated female ICR mouse skin at the doses of 2.5 and 5 mg twice per week for 16 weeks, 30 min prior to each promotion treatment with TPA. The protective effect of sericin was evident in terms of significant reduction in tumor incidence and tumor multiplicity at the doses of 2.5 and 5 mg per application, compared to the control group without receiving sericin. The expression of tumor necrosis factor (TNF)-alpha protein and the level of 4-hydroxynonenal (4-HNE) in normal epidermis were significantly reduced in both sericin treatment groups. In experiment 2, sericin at the dose of 5 mg was applied topically to the dorsal mouse skin 30 min before application of a TPA, and the same doses of TPA and sericin were applied twice at an interval of 24 h. Sericin treatment inhibited double TPA treatment-induced morphological changes reflecting inflammatory response, including leukocyte infiltration, hyperplasia and cell proliferation. Furthermore, sericin treatment significantly suppressed the elevation in 4-HNE level and elevated expressions of c-fos, c-myc and cyclooxygenase-2 (COX-2) in normal epidermis induced by double application of TPA. The results suggest that sericin possesses protective effect against tumor promotion in mouse skin by suppressing oxidative stress, inflammatory responses and TNF-alpha.