Hematoporphyrin derivative photodynamic therapy is evolving as a local treatment for neoplastic disease. The emphasis of previous research has been on the determination of mechanisms of tumoricidal activity and defining the tumoricidal porphyrin component in hematoporphyrin derivative. The effect of hematoporphyrin derivative photodynamic therapy on normal tissue has received little attention. In the following study we examined the morphological changes of normal rat intestine exposed to hematoporphyrin derivative and light. In this model a segment of rat jejunum was exposed to red light (greater than 590 nm; 360 J/cm2) 24 or 72 h after the i.v. administration of hematoporphyrin derivative (5 or 10 micrograms/g body weight). Control groups received either no treatment, hematoporphyrin derivative only, or light only. Four h after treatment, intestinal segments were removed and examined by light microscopy. Segments treated with hematoporphyrin derivative and light showed extensive sloughing of the mucosa and submucosa with sparing of the muscular and serosal layers. It appears that hematoporphyrin derivative photodynamic therapy is capable of causing mucosal and submucosal damage to normal rat jejunum at these doses of light and hematoporphyrin derivative.