Cranial osteomyelitis is a potentially fatal lesion. White blood cell scanning (WBC) with 99mTc-hexamethylpropylene amine oxime (HMPAO) has proven highly sensitive and specific in the diagnosis and follow-up of patients with suspected osteomyelitis. In this report we show the usefulness of SPECT and transmission CT performed simultaneously using a hybrid imaging device for the functional anatomic mapping of soft tissue and cranial bone infections. 99mTc-HMPAO-labeled leukocytes scintigraphy was performed on an elderly diabetic man with an intracranial mass lesion and with suspected temporal bone infection. Planar scans were acquired 30 min, 4 h, and 24 h after injection. SPECT/CT was obtained 6 h after tracer injection, using a dual-head camera coupled with a low-power X-ray tube. The scintigraphic results were matched with the results of surgery and of clinical follow-up. The planar images alone were true-positives for abscess in this patient. SPECT/CT improves the accuracy of99mTc-HMPAO scintigraphy especially in discriminating between soft-tissue and bone involvement. In fact, SPECT/CT also showed temporal bone osteomyelitis. This result indicates that SPECT/CT performed using a hybrid device can improve imaging with 99mTc-HMPAO-labeled leukocytes in patients with suspected osteomyelitis by providing accurate anatomic localization and precise definition of the extent of infection.