Acute cutaneous photosensitivity is a major manifestation of certain forms of human porphyria and also occurs in patients treated with hematoporphyrin derivative (HpD) photoradiation for the diagnosis and treatment of malignant tumors. In this study a quantitative animal model useful for in vivo studies of acute porphyrin photosensitization in cutaneous tissue was developed. C3H mice injected with HpD and irradiated 6 h later with 405 nm energy developed a 40-90% increase in ear thickness which was present immediately after irradiation and persisted for at least 24 h. No ear swelling occurred in animals receiving 405 nm radiation alone or HpD alone. Histologically, this photosensitivity reaction was manifest as edema, vascular dilatation, and mast cell degranulation immediately after irradiation followed by an influx of polymorphonuclear leukocytes and epidermal necrosis 24 h later. Tissue injury evoked by HpD and light was accompanied by extravasation of intravenously administered 125I-labeled albumin in the irradiated ears, indicating that photosensitization was accompanied by transudation of serum into the site of tissue injury. An in vivo correlation of this approach was verified by detection of measurable increase in ear thickness in irradiated mice rendered porphyric by the ingestion of a griseofulvin-containing diet. The mouse ear swelling model offers a useful system with which to study acute porphyrin photosensitization in the skin, and may lead to important new insights into the pathogenesis and prevention of this form of phototoxicity. © 1986.