OBJECTIVE: Photodynamic therapy (PDT) with two chlorin sensitisers was assessed on nude mice bearing human mesothelioma xenografts, and on intrathoracic tissues of minipigs with the same drug-light conditions to optimise the antitumour activity of PDT while preventing photosensitising injury to normal tissues. METHODS: Laser light (20 J/cm2) at 652 nm was delivered to the xenografts 1-4 days after i.p. administration of 0.1 mg/kg m-tetrahydroxyphenyl-chlorin (mTHPC) or an equimolar dose of polyethylene glycol-derived mTHPC (pegylated mTHPC), respectively. The extent of tumour necrosis was assessed by histomorphometry. Intraoperative PDT was then performed to the thoracic cavity of minipigs through a sternotomy with the same drug-light conditions at drug-light intervals ranging from 12 h to 6 days after i.v. administration of mTHPC and pegylated mTHPC, respectively. RESULTS: Both, mTHPC and pegylated mTHPC, resulted in photosensitised necrosis of mesothelioma xenografts at drug-light intervals from 1 to 4 days but the extent of necrosis was significantly larger by use of pegylated mTHPC instead of mTHPC at a drug-light interval of 3 and 4 days. The optimal tumourcidal effect was achieved with pegylated mTHPC at a drug-light interval of 4 days. The photosensitising effect of mTHPC on intrathoracic tissues of minipigs revealed severe damage of virtually all tissues except nerves at short drug-light intervals. Tissue damage gradually became less at longer drug-light intervals and was absent at intervals of 3 days and longer. In contrast, pegylated mTHPC resulted in no obvious change to any structure at any drug-light interval assessed. CONCLUSIONS: PDT with pegylated mTHPC reveals the potential of selective tumour destruction in this experimental setting and deserves further evaluation for intraoperative application in patients with malignant mesothelioma.