PURPOSE: A study of irradiated (0.25-2 Gy) murine bone marrow has investigated the relationships between apoptotic responses of cells exposed in vivo and in vitro and between in vivo apoptosis and tissue cytotoxicity. MATERIALS AND METHODS: The time course of reduction in bone marrow cellularity in vivo was determined by femoral cell counts and apoptosis measurements obtained using three commonly used assays. Inflammatory pro-apoptotic cytokine production at 24 h post-exposure in vivo was investigated using a bystander protocol. RESULTS: In vivo, there is a dose- and time-dependent non-linear reduction in bone marrow cellularity up to 24 h post- irradiation not directly represented by apoptosis measurements. The majority of cells are killed within 6 h but there is on-going cell loss in vivo up to 24 h post-irradiation in the absence of elevated levels of apoptosis and associated with the induction of cytokines produced in response to the initial tumor protein 53 (p53)-dependent apoptosis. CONCLUSION: The results demonstrate that small increases in measured apoptosis can reflect significant intramedullary cell death and with apoptotic processes being responsible for pro-inflammatory mechanisms that can contribute to additional on-going cell death. The findings demonstrate the importance of studying tissue responses when considering the mechanisms underlying the consequences of radiation exposures.