Photodynamic therapy (PDT) and hyperthermia have been investigated as treatments for several types of tumors. Studies have been done to determine the efficacy of each modality individually and recently in combination with each other. In this study 630 nm light was delivered by an argon-dye laser and hyperthermia was induced using a Nd:YAG laser. Both lasers offer the ability of delivering the beams through a quartz fiberoptic alone or simultaneously. This present study examines (a) the efficacy of the simultaneous administration of PDT and selective hyperthermia at 44.5°C in tumor control; (b) the effect of hyperthermia and PDT + hyperthermia on tumor and normal tissue microcirculation; and (c) the toxicity in normal tissue of PDT, hyperthermia and the simultaneous administration of the two modalities. Hyperthermia alone (44.5°C, 30 min) resulted in complete destruction of tumors with no subsequent regrowth in 12% of the mice treated. PDT alone (5 mg/kg DHE; 135 J/cm2) resulted in a cure rate of approximately 30%, and the simultaneous treatment of the modalities resulted in a 65% cure rate after 6 weeks. These values are indicative of a synergistic interaction. This study also examined the toxic effects of hyperthermia and the combination therapy to normal tissues in mice. Direct organ exposures produced much greater tissue damage than whole abdomen exposures, as expected, although there was no resulting lethality. Necrosis to a small degree occurred in the spleen and pancreas with hyperthermia alone, while extensive necrosis occurred in all of the organs with the combination. The extent of damage caused, however, was no greater than that caused by PDT alone in most tissues examined. Fluorescein angiography shows a lack of response in the surrounding normal tissue microcirculation for hyperthermia only. The combination treatments, however, shut down the microcirculation within the treatment field.