The therapeutic index of meta-tetrahydroxyphenylchlorin-mediated photodynamic therapy (mTHPC-PDT) was assessed in BALB/c nude mice bearing human malignant mesothelioma xenografts. Equal doses of 650 nm laser light were delivered to the tumour and to an equal-sized area of the hind leg (control site) after i.p. administration of mTHPC. Twenty-one groups of 6 animals each were treated under various drug-light conditions and at drug-light intervals ranging from 4 hr to 6 days. After light delivery the extent of tumour necrosis and the depth of alterations in normal tissue were assessed by light microscopy of standardized histological sections. A therapeutic index (TI) of mTHPC-PDT was defined as the cross-sectional area of tumour necrosis per depth of visible tissue injury at the control site. This TI was strongly related to the conditions of treatment. In particular, it was increased by prolonging the drug-light interval up to 5 days and by increasing the dose of light for any dose of drug. The most profound increase of TI was obtained by increasing the intensity of light administered at the chosen interval while reducing the dose of drug. Our findings suggest that threshold conditions operate in PDT and have important implications for clinical application of the treatment.