The purpose of this study was to evaluate whether topical application of superoxide dismutase with cell penetrating peptide (HIV-TAT) could protect against skin damage induced by UVB irradiation in humans. The permeability through stratum corneum of large proteins linked to TAT peptide was firstly confirmed by confocal microscopy and tape stripping. Ten healthy volunteers with either Fitzpatrick skin type II or III were recruited in this clinical study. TAT-SOD (300 units/cm2) and vehicle cream were applied on two symmetric areas of both inner upper arms 1 h prior to UVB irradiation. After one hour of pretreatment, subjects received 10 incremental doses of UVB on pretreated areas. 24 h later, erythema, blood flow and apoptotic cells were measured. Pretreatment with TAT-SOD 1 h prior to UVB radiation promoted a mean minimal erythema dose (MED) increase of 36.6 ± 18.4% (p = 0.013 < 0.05. n = 10) compared to vehicle control. The median blood flow values of all subjects following 2 and 3-MED of UVB were 107.8 ± 51.0 units and 239.5 ± 88.0 units respectively, which account for 26% and 25% decrease with respect to vehicle groups. These data suggest that TAT-SOD significantly suppresses UVB induced erythema formation and blood flow rise. Furthermore, pretreatment with TAT-SOD 1 h prior to 2-MED of UVB irradiation reduced the apoptotic sunburn cell formation by 47.6 ± 8.6% (p < 0.0001) in all subjects. Evaluating results generated from all measurements, we conclude that topical application of TAT-SOD significantly attenuates UVB-induced skin damage in man. These biological effects of TAT-SOD are probably mediated via its free radical scavenging properties, clearly differentiating it from other physical sunscreen agents.