Periprosthetic infection and aseptic prosthesis loosening remain the most common and serious complications of total hip arthroplasty and total knee arthroplasty. The differentiation of septic from aseptic prosthetic loosening is of great importance because the treatment of the two conditions is vastly different. Anatomical imaging procedures such as conventional radiography, computed tomography, or MRI are unable to differentiate septic and aseptic loosening, mainly because of hardware-induced artifacts. Nuclear imaging, however, reflects functional rather than anatomical changes and is not hampered by the presence of a metallic prosthesis. The commonly used nuclear imaging techniques include triple-phase bone scintigraphy, Ga-67, leukocyte scintigraphy, leukocyte/bone marrow scintigraphy, monoclonal antibodies/antibody fragments, radiolabeled ciprofloxacin, antimicrobial peptides, etc. Besides infection detection, single-photon emission computed tomography (SPECT) and PET with computed tomography (SPECT/CT and PET/CT) provide additional information on the location of the infection foci, which is clinically important for surgeons to select the most appropriate treatment and guide the intraoperative clearance of the infection foci. The current review will describe the working mechanism, clinical practice, and pros and cons of these techniques in the evaluation of periprosthetic infection. Nucl Med Commun 36: 305-311 Copyright (c) 2015 Wolters Kluwer Health, Inc. All rights reserved.