The effect of photodynamic therapy (PDT) on tumor growth as well as on tumor cell survival in vitro and in vivo was studied in the EMT-6 and RIF experimental mouse tumor systems. In vitro, RIF cells were more sensitive towards PDT than were EMT-6 cells when incubated with porphyrin (25 micrograms/ml, dihematoporphyrin ether) and subsequently given graded doses of light. In vivo, both tumor types responded to PDT (EMT-6, dihematoporphyrin ether, 7.5 mg/kg; RIF, dihematoporphyrin ether, 10 mg/kg; both followed 24 hr later by 135 J of light at 630 nm/sq cm) with severe vascular disruption and subsequent disappearance of tumor bulk. However, whereas the cure rate for EMT-6 tumors was 90%, it was 0% for RIF tumors. Raising the light dose to 200 J/sq cm resulted in 100% cures for EMT-6 tumors accompanied by damage to the surrounding tissues and 13% cures for RIF tumors. Tumor cell clonogenicity following PDT in vivo was assessed using the in vitro colony formation assay. In both tumors, it was found to be nearly unaffected by PDT if the tumor tissue was excised and explanted immediately following completion of treatment. This indicates that the effect of PDT on tumor cells directly was not sufficient to decrease tumor clonogenicity even at doses which led to total macroscopic tumor destruction. Where the tumors remained in situ following PDT and explantation was delayed for varying lengths of time (1 to 24 hr), tumor cell death occurred rapidly and progressively, indicating that tumor cell damage was expressed only if the cells remained exposed to the in situ environment after treatment. The kinetics and extent of tumor cell death were very similar for both tumor types despite their difference in cure rates. The reduction in tumor clonogenicity at 4 hr post-PDT closely matched that of tumor deprived of oxygen for the same period of time, implying that one of the major factors contributing to tumor destruction may be damage of the tumor circulation and the consequences of treatment-induced changes in tumor physiology.