Sepsis is primarily a disease of the aged, with 65% of sepsis cases reported in patients older than 65 years and 80% of deaths due to sepsis occurring in this age group. Klotho knockout mice (Klotho mice) are a mouse model of accelerated aging and shortened life span. The purpose of the study was to elucidate the immunological changes occurring in Klotho mice during sepsis. Five-week-old homozygous female Klotho knockout (Klotho) and wild-type (WT) mice were subjected to 1 × 27-gauge cecal ligation and puncture (CLP), and survival was compared after 4 days. Another set of mice was killed at 8 h after CLP or sham surgery, and the spleen, thymus, and serum were harvested. Apoptosis was measured by flow cytometry by using caspase 3. Serum cytokines and bacterial colony count in peritoneal lavage were also analyzed. Klotho septic mice started to die at 8 to 12 h after CLP, and the final survival of Klotho mice was significantly lower than that of WT mice (0% vs. 100%, P < 0.01). Increased bacterial count in the peritoneal cavity and decreased recruitment of neutrophils and macrophages to the peripheral cavity were observed in Klotho-CLP mice. Both flow cytometric and immunohistological analyses showed a dramatic increase in caspase 3–positive cells in the thymus and spleen of Klotho-CLP mice (P < 0.01). Serum concentrations of interleukin 6, tumor necrosis factor α, and interleukin 10 were higher in Klotho-CLP mice than in WT-CLP mice. Hypercytokinemia with impaired bacterial clearance and increased apoptosis of lymphocytes may be related to poor survival in Klotho-septic mice.