Intensive and exhaustive exercise induces an activation of blood T-lymphocytes which seems to be terminated by apoptotic processes in the post-exercise period. Here, we report that exercise induced T-lymphocyte apoptosis is a systemic phenomenon occurring in various lymphoid and non-lymphoid tissues. Apoptosis rate could be related to exercise intensity and type. While in some tissues such as the spleen and Peyer's patches an early start of apoptosis (1-3h post-exercise) could be detected, a delayed apoptosis (24h post-exercise) was observed in lung, bone marrow, and lymph nodes. Further analysis showed a similar apoptosis distribution among lymphocyte subpopulations. We tested whether components of the extrinsic or the intrinsic apoptotic pathways or both were involved in these processes. Elevated levels of lipid peroxidation-product malondialdehyde (MDA) indicating an increased production of reactive oxygen species (ROS) were found after exercise in Peyer's patches, lung and spleen but not in lymph nodes. Application of N-acetyl-cysteine (NAC) prevented exercise induced T cell apoptosis completely in spleen and bone marrow, partially in lung and Peyer's patches while it was ineffective in lymph nodes. Additionally, exercise addressed the Fas-mediated apoptosis. The percentage of Fas-receptor (Fas+) and Fas-ligand positive (FasL+) lymphocytes was enhanced in Peyer's patches after exercise. Moreover, FasL+ T cells were increased in the lung, while in lymph nodes Fas+ cells were increased. The critical role of Fas-signalling in exercise-induced apoptosis was supported by using Fas-deficient MRL/Lpr-mice. In Fas-deficient mice exercise induced T-lymphocyte apoptosis was prevented in spleen, lung, bone marrow and lymph nodes but not in Peyer's patches. These data demonstrate that exercise induced lymphocyte apoptosis is a transient systemic process with tissue-type specific apoptosis-inducing mechanisms whose relevance for the adaptive immune competence remains to be shown.