(1) Background: Treatment of cardiac arrhythmias and conduction disorders with the implantation of a cardiac implantable electronic device (CIED) may lead to complications. Cardiac device-related infective endocarditis (CDRIE) stands out as being one of the most challenging in terms of its diagnosis and management. Developing molecular imaging modalities may provide additional insights into CDRIE diagnosis. (2) Methods: We performed a systematic literature review to critically appraise the

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... nce for the diagnostic performance of the following hybrid techniques: single photon emission tomography with technetium99m-hexamethylpropyleneamine oxime-labeled autologous leukocytes (99mTc-HMPAO-SPECT/CT) and positron emission tomography with fluorodeoxyglucose (18F-FDG PET/CT). An analysis was performed in accordance with PRISMA and GRADE criteria and included articles from PubMed, Embase and Cochrane databases. (3) Results: Initially, there were 2131 records identified which had been published between 1971-2021. Finally, 18 studies were included presenting original data on the diagnostic value of 99mTc-HMPAO-SPECT/CT or 18F-FDG PET/CT in CDRIE. Analysis showed that these molecular imaging modalities provide high diagnostic accuracy and their inclusion in diagnostic criteria improves CDRIE work-up. (4) Conclusions: 99mTc-HMPAO-SPECT/CT and 18F-FDG PET/CT provide high diagnostic value in the identification of patients at risk of CDRIE and should be considered for inclusion in the CDRIE diagnostic process.