Objective  To explore the clinical characteristics of overwhelming post-splenectomy infection (OPSI) with main manifestation of severe sepsis. Methods  Clinical data of a patient with severe sepsis caused by OPSI was reported and analyzed and the clinical characteristics were investigated. Results  A 35-year-old male patient who underwent splenectomy two years before was admitted by the Department of Emergency of Renji Hospital South Campus due to headache and emesis. Examination results showed severe sepsis and the patient was diagnosed with OPSI and underwent anti-infectious treatment and symptomatic supportive treatment. After one week, the symptoms tended to be stable and the prognosis was good. Conclusion  The incidence of OPSI is low but the mortality is high. Clinicians should be fully aware of this disease, so as to make early diagnose and treatment and avoid delay.