Two sisters presented to our medical center with nontraumatic cerebrospinal fluid (CSF) fistulas from left sphenoid sinocranial junction defects. One sister had recurrent meningitis over a 20-year period that prompted a skull base evaluation. Four years later, her younger sister presented with profuse CSF rhinorrhea. Transethmoid sphenoidotomy with sinus obliteration and lumbar-subarachnoid temporary CSF diversion successfully treated one sister, while the other required reoperation and permanent lumbar-peritoneal shunting. In both cases the skull base defect was identically located in the posterolateral left sphenoid sinus. Embryological considerations, evaluation, and management are presented.