Diagnosis and follow-up of skull infections are usually performed by neurologic examination, laboratory tests and instrumental diagnostic methods such as computed tomography (CT) and magnetic resonance imaging (MRI). These have, however, shown some limitations for specificity. The aim of the current study was to evaluate the overall contribution of Tc-99m exametazime-labeled leukocyte imaging scan Tc-99m hexamethylpropyleneamine (HMPAO) labeled white blood cells (WBC) in the diagnosis and management of infections in skull neurosurgery. Thirty-four patients were subdivided into 4 groups on the basis of the suspected pathology: intracerebral lesions on CT or MRI (group A, n = 20), suspected postsurgical infections (group B, n = 6), suspected deep infection of the surgical wound (group C, n = 4), and suspected infection of the ventriculoperitoneal shunt (group D, n = 4). All patients underwent CT, MRI, and Tc-99m HMPAO WBC imaging. Patients in group C also underwent bacteriologic and culture examinations of wound secretions if present. In positive cases in group A, Tc-99m HMPAO WBC imaging was repeated. The scintigraphic results were compared with histologic findings in patients who underwent surgery and with the results of a 12-month clinical follow-up in the remaining patients. Tc-99m HMPAO WBC scans correctly detected the infections in all groups. Furthermore, such imaging proved to be able to document recovery from the disease in all of the assessed cerebral abscesses. This study may have an important role both in the diagnosis and in the management of infections in skull neurosurgery, which, it is hoped, will be confirmed in the future.