Caspase-8 is best known for its cell death function via death receptors. Recent evidence indicates that caspase-8 also has nonapoptotic functions. Caspase-8 deficiency is associated with pathologies that are unexpected for a proapoptotic molecule, such as abrogation of activation-induced lymphocyte proliferation, perturbed immune homeostasis, and immunodeficiency. In this study, we report the long-term physiological consequences of T cell-specific deletion of caspase-8 (tcasp8-/-). We show that tcasp8-/- mice develop an age-dependent lethal lymphoproliferative and lymphoinfiltrative immune disorder characterized by lymphoadenopathy, splenomegaly, and accumulation of T cell infiltrates in the lungs, liver, and kidneys. Peripheral casp8-/- T cells manifest activation marker up-regulation and are proliferating in the absence of any infection or stimulation. We also provide evidence suggesting that this immune disorder is different from the autoimmune lymphoproliferative syndrome. Interestingly, the condition described in tcasp8-/- mice manifests features consistent with the disorder described in humans with Caspase-8 deficiency. These findings suggest that tcasp8-/- mice may serve as an animal model to evaluate Caspase-8-deficient patient prognosis and therapy. Overall, our study uncovers novel in vivo functions for caspase-8 in immune regulation.