Genetic lesions and cell death associated with exposure to ionizing radiation have generally been attributed to DNA damage arising as a consequence of deposition of energy in the cell nucleus. However, reports of radiation-induced bystander effects, in which DNA damage is produced in nonirradiated cells as a consequence of communication with irradiated cells, indicate additional mechanisms. At present, most information has been obtained using in vitro systems, and the in vivo significance of bystander factors is not clear. In this study we show that signals generated in vivo in the bone marrow of CBA/Ca mice irradiated with 4 Gy gamma rays 24 h previously, but not immediately postirradiation, are able to induce DNA damage and apoptosis in nonirradiated bone marrow cells. The signaling mechanism involves FasL, TNF-alpha, nitric oxide and superoxide and macrophages are implicated as a source of damaging signals. Such delayed bystander-type damage demonstrates the importance of studying tissue responses subsequent to the radiation exposure as well as effects at the time of irradiation when considering the mechanisms underlying the consequences of radiation exposures.