Abstract Background Metastatic involvement of non-regional supraclavicular or superior mediastinal lymph nodes in distal oesophageal cancer is rare, but has important implications for prognosis and management. The management of non-regional lymph nodes which appear indeterminate on CT and FDG PET-CT (subcentimetre nodes or those with preserved normal morphology, but increased FDG avidity) can present a diagnostic dilemma. This study investigates the incidence, work-up, and clinical significance of non-regional clinically indeterminate FDG avid lymph nodes. Methods A single centre retrospective review of all FDG PET-CT scans conducted over 5 years was conducted. Patients with mid- or distal oesophageal cancer with non-regional FDG avid nodes were identified. Subsequent work-up, management, and outcomes were retrieved from electronic health records. Results Reports for 1189 PET-CT scans were reviewed. A total of 79 patients met the inclusion criteria. Of these, 18 (23%) were deemed to have disease and performance status potentially amenable to radical surgery, and underwent further assessment. The indeterminate lymph nodes were successfully sampled via endobronchial ultrasound (EBUS) or ultrasound-guided fine needle aspiration (US-FNA) in 100% of cases. 15/18 (83.3%) of samples were benign and proceeded to surgery. Outcomes for patients who proceeded to surgery were similar to other cohorts. None had pathology suggesting false negative lymph node sampling. Conclusions EBUS and US-FNA are effective means of sampling clinically indeterminate non-regional lymph nodes, and can significantly impact prognosis, and management. Further investigations in this context are of value in this cohort and should be pursued.