Ultraviolet B (UVB) irradiation exerts hazardous effects such as acute photodamage, skin cancer and photoaging. In this study we evaluated the protective effects of a nonsedative histamine H1-receptor antagonist, mizolastine, on UVB-exposed skin dermal fibroblasts. Therefore, primary human skin fibroblasts were incubated with mizolastine or dexamethasone after 100 mJ/cm² UVB irradiation. Leukotriene B4 (LTB4) in fibroblast supernatants was detected with enzyme immunoassays, expression of 5-lipoxygenase (5-LOX) messenger RNA (mRNA) in skin fibroblasts was examined by reverse transcriptase–polymerase chain reaction and expression of 5-LOX protein was measured by immune blotting and immunofluorescent staining with rabbit anti-human 5-LOX antibody. It was found that 0.01 mM mizolastine inhibited UVB-induced LTB4 production from skin fibroblasts at 12, 24 and 36 h. Meanwhile, mizolastine down-regulated 5-LOX mRNA expression and inhibited 5-LOX translocation from nucleus to cytoplasm in fibroblasts. On the basis of these findings, we propose that mizolastine might play a protective role in the pathogenesis of UV radiation–induced acute photodamage of the skin.