Background Patients who developed myocarditis following SARS-CoV-2 vaccination show abnormalities on cardiac MRI. However, whether myocardial changes occur in asymptomatic individuals following vaccination is not well established. Purpose To assess myocardial ¹⁸Fluorine-fluorodeoxyglucose (¹⁸F-FDG) uptake on PET/CT in asymptomatic SARS-CoV-2 vaccinated patients compared to nonvaccinated patients. Materials and Methods This retrospective study included patients who underwent ¹⁸F-FDG PET/CT for indications unrelated to myocarditis during the period before (11/1/2020 - 2/16/2021) and after (2/17/20121 - 3/31/2022) SARS-CoV-2 vaccines were available. Myocardial and axillary FDG uptake were quantitatively assessed using maximum standardized uptake value (SUVmax). SUVmax values in all patients and in patients stratified by sex (male/female), age (<40, 41-60, >60 years), and time interval between vaccination and PET/CT were compared using Mann-Whitney U test or Kruskal-Wallis test with post ad -hoc Dwass, Steel, Critchlow-Fligner multiple comparison analysis. Results The study included 303 nonvaccinated patients (mean age, 52.9 years ± 14.9 [SD]; 157 females) and 700 vaccinated patients (mean age, 56.8 years ± 13.7 [SD]; 344 females). Vaccinated patients had overall higher myocardial FDG uptake compared to nonvaccinated patients (median SUVmax, 4.8 [IQR: 3.0-8.5] vs median SUVmax, 3.3 [IQR: 2.5-6.2]; P < .0001). Myocardial SUVmax was higher in vaccinated patients regardless of sex (median range, 4.7-4.9 [IQR: 2.9-8.6]) or patient age (median range, 4.7-5.6 [IQR: 2.9-8.6]) compared to corresponding nonvaccinated groups (sex median range, 3.2-3.9 [IQR: 2.4-7.2]; age median range, 3.3-3.3 [IQR: 2.3-6.1]; P range, <.001-.015). Furthermore, increased myocardial FDG uptake was observed in patients imaged 1-30, 31-60, 61-120, and 121-180 days after their second vaccination (median SUVmax range, 4.6-5.1 [IQR: 2.9-8.6]) and increased ipsilateral axillary uptake was observed in patients imaged 1-30, 31-60, 61-120 days after their 2nd vaccination (median SUVmax range, 1.5-2.0 [IQR: 1.2-3.4]) compared to the nonvaccinated patients (P range, <.001-<.001). Conclusion Compared to nonvaccinated patients, asymptomatic patients who received their 2nd vaccination 1-180 days prior to imaging showed increased myocardial FDG uptake on PET/CT. See also the editorial by Bluemke in this issue.