When the middle ear becomes chronically infected despite myringotomy tubes and antibiotics, a mastoidectomy be be recommended. The procedure is generally performed under anesthesia, but commonly on an outpatient basis. In most cases, the surgeon makes an incision in the crease behind the ear. Using an operating microscope to see the fine structures of the middle ear space, the surgeon drills away the porous bone behind the ear. This bone normally contains air pockets in healthy individuals but may be replaced with chronic infection or destroyed by an expanding skin cyst (cholesteatoma). The surgeon drills down until the critical normal structures are identified: the temporal lobe of the brain, the sigmoid sinus that drains into the jugular vein, the facial nerve, and the bones of the middle ear. If necessary, the middle ear bones are sculpted and reconfigured or replaced with man-made prostheses. The eardrum is repaired if possible. Recovery is generally less than a week.

Mastoidectomy with repair of the eardrum and the bones of the middle ear (ossicular chain), can sometimes restore hearing to those with conductive hearing loss due to chronic infections. The primary goal for surgery is to eradicate the infection, even if hearing cannot be restored. The risks of surgery include further damage to the hearing, paralysis of facial nerve, and alteration of taste. Other risks of any surgery include pain, persistent infection, bleeding, and general anesthesia.