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Background/Objectives In embolic stroke of undetermined source (ESUS) 18F-Fluorodeoxyglucose positron emission tomography (18F-FDG-PET) may have a role in detecting several conditions, including malignancies. Currently, there are limited data and no guidelines to inform the use of 18F-FDG-PET in patients with ESUS.Method This retrospective cohort study encompassed all public neurology inpatients in South Australia during a two-year period. Patients admitted with ESUS who received an 18F-FDG-PET were included in the study and underwent case note review for clinical, laboratory, and imaging features that may be associated with malignancy or 18F-FDG-PET abnormalities. Cases in which there was a high suspicion of infective endocarditis were excluded.Results Of 6,786 eligible cases, 36 fulfilled inclusion criteria. In these patients, 8/36 (22.2%) had a significant abnormality on 18F-FDG-PET, all of which were malignancy. These findings informed the stroke aetiology in 7/8 (87.5%) cases. In 7/8 (87.5%) of these cases, the positive 18F-FDG-PET was preceded by alternative imaging evidence of a significant abnormality. The one case without a prior radiological abnormality was due to endometrial cancer. Of those with the three-territory sign, 75% (3/4) had a positive 18F-FDG-PET. Conversely, 90.9% (10/11) of cases with other systemic vascular events had no significant abnormalities on 18F-FDG-PET.Conclusion In this cohort, nearly all cases with significant abnormalities detected on 18F-FDG-PET in patients with ESUS were preceded by other radiological findings suggestive of a significant abnormality.