TRAIL/Apo-2 L, a member of the Tumor Necrosis Factor cytokine family, induces apoptosis specifically in malignant cells. A combination of TRAIL and radiation is highly synergistic in in vitro experiments. In addition to this additive effect, we observed that TRAIL is induced by irradiation of certain cell lines. The induction begins approximately 2 hours after irradiation. This might even enhance the antineoplastic effect of ionizing radiation and partially explain the abscopal effect observed in hematopoietic malignancies. TRAIL levels were evaluated in 17 patients treated with radiation for Hodgkin's and non-Hodgkin's lymphoma. We did not observe a specific TRAIL expression pattern that could be correlated with histology, disease status, volume of disease, radiation dose, and other antineoplastic therapies, but a definite pattern observed in a single patient remained constant over time. TRAIL and interferons display a common pattern of gene expression at certain nodal points of interaction between the two physiologic pathways. Our hypothesis is that the radiation-induced changes in TRAIL expression observed in patients undergoing therapeutic radiation may be emblematic of the various physiologic pathways induced or inhibited by ionizing radiation and may even be partially responsible for the "bystander effect" observed in unirradiated cells in close proximity to irradiated cells.