Haemopoietic tissues exposed to ionizing radiation are shown to exhibit increased macrophage activation, de®ned by ultrastructural characteristics and increased lysosomal and nitric oxide synthase enzyme activities. Macrophage activation post-irradiation was also associated with enhanced respiratory burst activities and an unexpected neutrophil in®ltration. Examination of p53-null mice demonstrated that macrophage activation and neutrophil in®ltration were not direct e ects of irradiation, but were a consequence of the recognition and clearance of radiation-induced apoptotic cells. Increased phagocytic cell activity was maintained after apoptotic bodies had been removed. These ®ndings demonstrate that, contrary to expectation, recognition and clearance of apoptotic cells after exposure to radiation produces both a persistent macrophage activation and an in¯am-matory-type response. We also demonstrate a complexity of macrophage activation following radiation that is genotype dependent, indicating that the in vivo macrophage responses to radiation damage are genetically modi®ed processes. These short-term responses of macrophages to radiation-induced apoptosis and their genetic modi®cation are likely to be important determinants of the longer-term consequences of radiation exposure. Furthermore, in addition to any e ects attributable to immediate radiation-induced damage, our ®ndings provide a mechanism for the production of damage via a`bystander' e ect which may contribute to radiation-induced genomic instability and leukaemogenesis. Oncogene (2001) 20, 7085 ± 7095.