BACKGROUND and OBJECTIVE: Since there is no satisfactory treatment modality for diffuse malignant mesothelioma of the chest, we assessed surgical tumor resection followed by intraoperative photodynamic therapy with mTHPC in a phase I study. STUDY DESIGN/MATERIALS and METHODS: Since 1990, eight patients have undergone intraoperative photodynamic therapy with m-tetrahydroxyphenylchlorin (mTHPC-PDT) following thoracotomy and surgical tumor resection. RESULTS: mTHPC-PDT-mediated tumor necrosis was characterized by tumor infarction due to tumor vessel necrosis and thrombosis, and its extent depended on drug-light conditions; 650 nm light delivered at 0.1 W/cm2 for 10 J/cm2 48 h after iv administration of 0.3 mg mTHPC/kg resulted in a 10-mm-deep complete tumor necrosis. Skin photosensitivity was related to the drug dose applied and occurred up to 17 days after iv administration of 0.3 mg mTHPC/kg, mTHPC-PDT of brachial plexus infiltrated by mesothelioma resulted in pain relief without deterioration of nerve function. CONCLUSION: Tumor resection and intraoperative mTHPC-PDT of the chest cavity is feasible under clinical conditions and offers local tumor control of sites involved. However, distant tumor spread was not prevented by this combined treatment modality and optimization of mTHPC-PDT is warranted for further intraoperative application.