In this report, we describe two cases of overwhelming post-splenectomy infection (OPSI). The first case was in a 70-year-old man who received a splenectomy in 2012 due to pancytopenia induced by hepatic cirrhosis. He presented with fever and fatigue. A blood test and abdominal ultrasonography were performed. However, these examinations did not indicate any abnormal findings. He unexpectedly suffered from septic shock and acute renal failure the following day. Treatment consisted of mechanical ventilation, broad-spectrum antibiotics and continuous hemodiafiltration. Despite intensive treatment, he died 3 days after the initial visit. The second case was in a 55-year-old man with end-stage renal failure who started hemodialysis in 2004 and received a splenectomy in 2005 because of splenic artery aneurysm rupture. He presented with headache and nausea. A blood test indicated bacterial infection. We suspected OPSI and treated him with broad-spectrum antibiotics, continuous hemodiafiltration and mechanical ventilation. Despite treatment, his general condition gradually deteriorated, and he died 15 days after the initial visit. In view of the high mortality rate, prevention through vaccination and provision of proper information regarding OPSI is important.