© 2014 The Society for Investigative Dermatology. UVB-induced DNA damage has a critical role in the development of photoimmunosuppression. The purpose of this study was to determine whether repair of UVB-induced DNA damage is regulated by Toll-like receptor-4 (TLR4). When TLR4 gene knockout (TLR4 -/-) and TLR4-competent (TLR4 +/+) mice were subjected to 90 mJ cm -2 UVB radiation locally, DNA damage in the form of cyclobutane pyrimidine dimers (CPDs) was repaired more efficiently in the skin and bone marrow-derived dendritic cells (BMDCs) of TLR4 -/- mice in comparison to TLR4 +/+ mice. Expression of DNA repair gene XPA (xeroderma pigmentosum complementation group A) was significantly lower in skin and BMDCs of TLR4 +/+ mice than TLR4 -/- mice after UVB exposure. When cytokine levels were compared in these strains after UVB exposure, BMDCs from UV-irradiated TLR4 -/- mice produced significantly more interleukin (IL)-12 and IL-23 cytokines (P<0.05) than BMDCs from TLR4 +/+ mice. Addition of anti-IL-12 and anti-IL-23 antibodies to BMDCs of TLR4 -/- mice (before UVB exposure) inhibited repair of CPDs, with a concomitant decrease in XPA expression. Addition of TLR4 agonist to TLR4 +/+ BMDC cultures decreased XPA expression and inhibited CPD repair. Thus, strategies to inhibit TLR4 may allow for immunopreventive and immunotherapeutic approaches for managing UVB-induced cutaneous DNA damage and skin cancer.