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Surgery is the first-line treatment for patients with an operable glioblastoma multiforme. Most commonly, the tumor is removed by a neurosurgeon using a surgical procedure called a craniotomy. This procedure involves removing a portion of the skull to expose the brain and gain access to the tumor. Once the tumor has been removed, the surgeon replaces the segment of the skull bone that had been previously removed and fastens it to the skull with metal screws and plates. Patients who have undergone a craniotomy will usually remain in the hospital for about a week to recuperate from the surgery.

In some cases, the surgeon may elect to access the brain tumor by performing a surgical procedure called a craniectomy. During this procedure, a portion of the skull bone is also removed to expose the brain, however, unlike with a craniotomy, the segment of the skull bone that has been removed is not replaced immediately after the brain tumor has been removed. The surgeon may perform a craniectomy instead of a craniotomy if the patient's skull bone cannot be reused or if the surgeon expects an excessive amount of swelling to occur after the tumor has been removed. If the piece of skull bone that has been removed during a craniectomy can be reused at a later time, the bone is frozen and is used at a later time to fill-in the defect (gap) in the skull. If the excised piece of skull bone cannot be reused, the surgeon will use a special material such as methylmethacrylate or hydroxyapatite bone cement as an implant to fill-in the skull defect. Patients will receive detailed instructions from the surgeon for protecting the soft-spot in the skull during the time interval between a craniectomy and reconstructive surgery to replace the missing piece of skull bone.

A primary objective in the surgical management of patients with glioblastoma multiforme is to debulk as much of the volume of the tumor as possible without damaging vital areas of the brain that control critical sensory and motor functions. One of the most important decisions a neurosurgeon has to make in planning the surgical removal of a brain tumor is how much of the tumor volume can be safely removed without causing the patient to suffer significant neurological deficits. Important factors that the neurosurgeon will take into consideration in planning brain surgery are the location and size of the tumor as well as the patient's age and overall status of health. Ideally, the most effective surgical treatment for glioblastoma multiforme is the removal of the entire tumor. If the neurosurgeon determines that it is not possible to debulk the entire tumor, he/she will elect to remove only a portion of the tumor. Partial tumor resection, however, is less effective than complete removal of the tumor and the risk of recurrence with partial tumor removal is much higher.

In general, in the era of modern neurosurgery and in the hands of an experienced neurosurgeon, a craniotomy with subsequent debulking of a brain tumor is considered to be a relative safe surgical procedure. It has been reported that major neurological complications associated with this type of surgery, persisting for longer than one-month or requiring aggressive treatment, occur in less than 10% of cases. Nevertheless, other complications resulting from brain tumor surgery have been reported to occur in about 25% to 35% of patients and include: