Glutathione S-transferases (GSTs) play a primary role in cellular defense against electrophilic chemical species and radical oxygen species. Because free radical attack is one mechanism of UV irradiation-caused skin damage, we investigated whether genetic variation at the GST loci GST T1 and GST M1 influences individual UVB sensitivity. In a double-blind clinical trial, 50 healthy volunteers were evaluated for minimal erythema dose of UVB irradiation, MED (J/cm2), skin types were assigned, and internal standard-controlled polymerase chain reaction (PCR) was used to identify their GST T1 and GST M1 genotypes. The five homozygous carriers of the GST T1 deletion (GST T1*0/0) presented with the most intensive inflammatory reactions after irradiation; they were significantly overrepresented among the highly UVB-sensitive subgroups (p = 0.006). Lack of GST M1 (GST M1*0/0, n = 27) tended to be more frequent only in UVB-sensitive subjects, and the proportion of the active GST M1 allelic variants *A and *B was similar in all UVB sensitivity subgroups. Three subjects with deficiencies in GST T1 and GST M1 had the most intense inflammatory responses. No effect of gender or genetic variations at the MC1R gene locus was established. Thus, heritable GST T1 deficiency may be a genetic determinant of individual skin sensitivity toward UV irradiation.