Technetium-99m hexamethylpropylene amine oxime (HMPAO)-labeled leukocytes are well established for the investigation of inflammatory disease. Their kinetics and normal distribution are similar to those of indium-111-labeled leukocytes except for nonspecific activity in urine, kidneys, gall bladder, and bowel, which results from the elution of secondary 99mTc-labeled HMPAO complexes. The principal clinical indications for [99mTc]HMPAO-leukocytes include inflammatory bowel disease (IBD), osteomyelitis, soft tissue sepsis, and, to a lesser extent, occult fever. The superior resolution and count density of 99mTc places [99mTc]HMPAO-leukocytes at an advantage over 111In-leukocytes in IBD, especially for the identification of small bowel involvement in patients with Crohn's disease. However, quantification of disease activity is more difficult than with 111In. Technetium-99m HMPAO-leukocytes are indicated for most forms of acute soft tissue and abdominal sepsis, although when compared with 111In, it may be more difficult to demonstrate communication between an abdominal abscess and bowel lumen. Chronic osteomyelitis, including infected joint prostheses, are better approached with 111In-labeled leukocytes. Occult fever and fever of unknown origin (FUO) are more controversial. There is still a place for gallium-67 in FUO, of which there is a wide spectrum of causes. Occult fever implies a pyogenic cause for an undiagnosed fever and should probably be imaged with 111In-leukocytes. With the advances being made in other imaging modalities and in interventional radiology, there is a clear need for radionuclide agents that can be used for whole-body screening in patients with undiagnosed fever. Such agents may include fluorine-18-fluorodeoxy-glucose and radiolabeled monoclonal antibodies to endothelial adhesion molecules activated at the foci of inflammation.