We report three extremely rare cases of Streptococcus pneumoniae meningoencephalitis (SPM) after trans-sphenoidal surgery (TSS). Between 2004 and 2010, we experienced three cases of severe SPM after surgery out of 1,965 patients undergoing TSS (0.15%). The three cases included a 4-year-old boy with a large cystic craniopharyngioma, a 40-year-old man with a non-functioning pituitary adenoma, and a 55-year-old man with acromegaly. The similarity among these SPM patients was that severe clinical events occurred suddenly 1-2 months postoperatively without any history of sinusitis or pneumonia. Despite intensive care these patients notably had residual neurological sequelae. In no case was rhinorrhea associated with SPM. It should be noted that SPM was not detected from bacterial cultures of the sphenoidal sinus mucous membranes (BCSM) obtained during TSS in two of the patients examined. Severe postoperative SPM can occur suddenly without cerebrospinal fluid (CSF) leakage within 2 months after surgery and requires emergency treatment. Reduced resistance to infection may play a role in the occurrence of SPM in our three patients. Our study indicates that BCSM is not useful for predicting postoperative meningitis.