We investigated whether the topical application of a novel, water-soluble γ-tocopherol (γ-Toc) derivative, γ-tocopherol-N,N-dimethylglycinate hydrochloride (γ-TDMG), could protect against UV-induced skin damage in hairless mice. Topical pre-or post-application of a 5% (93 mM) γ-TDMG solution in water/propylene glycol/ethanol (2:1:2) significantly prevented sunburn cell formation, lipid peroxidation and edema/inflammation that were induced by exposure to a single dose of UV irradiation of 5 kJ/m2 (290–380 nm, maximum 312 nm). This effect was greater than that seen with two α-Toc derivatives, α-tocopherol acetate (α-TA) and α-tocopherol-N,N-dimethylglycinate (α-TDMG). When a 5% solution of γ-TDMG was applied to mouse skin for 1 h, cutaneous γ-Toc increased by 25-fold after 24 h; levels of cutaneous α-Toc increased by only two-and eight-fold in α-TDMG and α-TA treated skins, respectively. These findings indicated that γ-TDMG immediately converted to γ-Toc in the skin and suggest that ability of γ-TDMG to protect the skin from the damaging effects of irradiation was due to its conversion to γ-Toc. When a 5% solution of γ-Toc was applied to mouse skin for 1 h, cutaneous γ-Toc rapidly increased by 25-fold, but fell to baseline levels by 24 h. In contrast, the concentration of γ-Toc in skin that was treated with γ-TDMG similarly increased, but these high levels were maintained after 24 h. These results suggest that γ-TDMG may be a more effective source of γ-Toc in skin. Thus, the topical application of γ-TDMG may be efficacious for the prevention of UV-B-induced skin damage.