An overwhelming post-splenectomy infection (OPSI) is a rare but rapidly fatal infection occurring in individuals following removal (or permanent dysfunction) of the spleen. The infections are typically characterized by either meningitis or sepsis, and are caused by encapsulated organisms including Streptococcus pneumoniae. It is a medical emergency and requires immediate treatment. Death has been reported to occur within 12 hours.

The spleen is necessary for protection against encapsulated bacteria (see Mechanism) and as such when removed by splenectomy it can lead to rapid unchallenged infection by encapsulated bacteria. The rapid progression from mild viral symptoms to sepsis is one of the things that makes OPSI particularly dangerous.

Another source of infection are species of Babesia, which are tick-borne parasites that cause babesiosis. Infection with Capnocytophaga canimorsus after dog bites can also cause the condition.