Hematoporphyrin derivative also known as Photofrin-I (Pf-I) and its more active dimeric tissue localizing component dihematoporphyrin ether, also known as Photofrin-II (Pf-II), are currently used in the diagnosis and management of a variety of epithelial neoplasms, in a modality known as photodynamic therapy (PDT).One of the drawbacks of these porphyrins for PDT is their ability to evoke prolonged cutaneous photosensitization. The mechanism of tumor ablation and cutaneous photosensitization by these photosensitizers is thought to relate to thegeneration of one or more reactive oxygen species such as superoxide anion, singlet oxygen and hydroxyl radical. However, the role of none of these oxygen species has been established unequivocally. In this study, groups of C3H mice were injected intraperitoneally with Pf-I or with Pf-II (5 mg/kg). Four hours after treatment with the photosensitizer, animals were divided into four groups and treated with a superoxide dismutase (SOD) mimic, bis [(3, 5 diisopropyl salicylato)(0, 0)Jcopper (II) (80 mg/kg body wt. in olive oil), β-carotene (133 mg/kg in olive oil) and dimethyl sulfoxide (0.3 ml/mouse in olive oil) or olive oil alone. Six hours after injection of the photosensitizer all of the mice were irradiated with visible radiation from a 4 KW metal halide light source for 2.5 hrs. Immediately after the irradiation ear swelling was measured as a marker of cutaneous photosensitization. The mice treated with Pf-I or Pf-II and light demonstrated two-fold enhancement of ear swelling whereas animals treated with the SOD mimic, β-carotene and DMSO had considerably less ear swelling (p < 0.01). The order of protective effects was SOD mimic > dimethyl sulfoxide > β-carotene. The observed protective effect was dependent on the dose of each quencher. The histopathologic evaluation of sections of ears of Pf-I and Pf-II treated photosensitized mice revealed vascular ectasia, dermal edema, neutrophilic infiltrate, increased mast cells, and mast cell degranulation. These effects were significantly alleviated by SOD mimic in both Pf-I and Pf-II treated mice. The protection was more pronounced with Pf-II as compared to Pf-I. β-carotene and DMSO afforded lower protection than that which occurred with SOD mimic. These data provide the first in vivo evidence for the involvement of superoxide anion in cutaneous porphyrin photosensitization. Furthermore, the greater protection against ear swelling by SOD mimic in the Pf-II treated animals suggests a more important role for superoxide anion in Pf-II mediated photosensitization. © 1988 SPIE.