UVB radiation is a potent immunosuppressive agent that inhibits cell-mediated immune responses. The mechanisms by which UVB radiation influences cell-mediated immune responses have been the subject of extensive investigation. However, the role of innate immunity on photoimmunological processes has received little attention. The purpose of this study was to determine whether Toll-like receptor-4 (TLR4) contributed to UV-induced suppression of contact hypersensitivity (CHS) responses. TLR4 -/- and wild type C57BL/6 (TLR4 +/+) mice were subjected to a local UVB immunosuppression regimen consisting of 100 mJ/cm 2 UVB radiation followed by sensitization with the hapten DNFB. Wild type TLR4 +/+ mice exhibited significant suppression of contact hypersensitivity response, whereas TLR4 -/- developed significantly less suppression. The suppression in wild type TLR4 +/+ mice could be adoptively transferred to naïve syngeneic recipients. Moreover, there were significantly fewer Foxp3 expressing CD4 +CD25 + regulatory T-cells in the draining lymph nodes of UV-irradiated TLR4 -/- mice than TLR4 +/+ mice. When cytokine levels were compared in these two strains after UVB exposure, T-cells from TLR4 +/+ mice produced higher levels of IL-10 and TGF-β and lower levels of IFN-γ and IL-17. Strategies to inhibit TLR4 may allow us to develop immunopreventive and immunotherapeutic approaches for management of UVB induced cutaneous immunosuppression. © 2011 Elsevier Inc. All rights reserved.