A 22-year-old man complaining of persisting high fever and right hypochondralgia was admitted to our hospital for infectious mononucleosis with splenic infarction detected by computed tomography. The splenic infarction deteriorated with a marked elevation of inflammatory parameters. This necessitated the commencement of methylprednisolone pulse therapy, resulting in prompt amelioration of inflammation and a reduction in cytokine levels. Including our case, only 9 cases of mononucleosis with splenic infarction have been reported to date; however, splenic infarction should be considered because it is a significant complication of infectious mononucleosis.