A mandatory differential diagnosis between postoperative granulomas and tumor recurrence is required whenever space-occupying lesions are detected at the surgical site, few months after removal of the intracranial neoplasm, because these two pathologies can often mimic each other clinically, by imaging techniques and even macroscopically. Since history or signs of inflammation may be lacking, and neurological complaints are generally nonspecific, a thorough imaging investigation is usually the only way to diagnosis. Herein we discuss the pathological basis and timing of granuloma formation along with the imaging characteristics and nuclear medicine findings necessary to confirm or exclude the diagnosis of tumor recurrence. In conclusion, the high sensitivity of positron emission tomography and the wide availability of single photon emission tomography can identify certain parameters (isometabolism, uptake in macrophages, etc.) to support differential diagnosis between postoperative granulomas and tumor recurrence.