In vitro treatment of human lung adenocarcinoma cells A549 with photofrin-based photodynamic therapy (PDT) resulted in the potentiation of macrophage-mediated killing of these cells assayed either by measuring 3H-thymidine release from the prelabeled target cells, or by determining the survival of A549 cells based on colony formation. The effector cells in these experiments were human promyelocytic leukemia cells HL60 induced to differentiate into macrophages. Very similar results were obtained with the murine squamous carcinoma SCCVII cells treated with PDT and subsequently admixed with mouse peritoneal macrophages. This effect increased with PDT dose and reached its maximum (i.e. complete or nearly complete release of the radioactive label) with the photodynamic treatment that was lethal to 40-50% of cells. In contrast, the PDT treatment of normal mouse kidney cells resulted in only a very limited enhancement of their cytolysis by mouse peritoneal macrophages. The exposure of A549 cells to X-ray irradiation had not affected the macrophage-mediated killing of these cells. The PDT survival curves of A549 cells cultured either alone or with the effector cells showed that the presence of macrophages even at very low effector: target cells ratios enhanced the PDT response of tumor cells. The enhancement ratio of 3.6 (at S = 0.01) was achieved with the effector: target cell ratio 2.5:1, which was the highest ratio tested with this assay. It is suggested that macrophages may recognize potentially repairable damage induced by PDT in tumor cells (presumably lipid fragments exposed in damaged cellular membranes), which helps them to identify the affected cells as their targets.