ObjectivesTo develop and test a Retina U-Net algorithm for the detection of primary lung tumors and associated metastases of all stages on FDG-PET/CT.MethodsA data set consisting of 364 FDG-PET/CTs of patients with histologically confirmed lung cancer was used for algorithm development and internal testing. The data set comprised tumors of all stages. All lung tumors (T), lymphatic metastases (N), and distant metastases (M) were manually segmented as 3D volumes using whole-body PET/CT series. The data set was split into a training (n= 216), validation (n= 74), and internal test data set (n= 74). Detection performance for all lesion types at multiple classifier thresholds was evaluated and false-positive-findings-per-case (FP/c) calculated. Next, detected lesions were assigned to categories T, N, or M using an automated anatomical region segmentation. Furthermore, reasons for FPs were visually assessed and analyzed. Finally, performance was tested on 20 PET/CTs from another institution.ResultsSensitivity for T lesions was 86.2% (95% CI: 77.2–92.7) at a FP/c of 2.0 on the internal test set. The anatomical correlate to most FPs was the physiological activity of bone marrow (16.8%). TNM categorization based on the anatomical region approach was correct in 94.3% of lesions. Performance on the external test set confirmed the good performance of the algorithm (overall detection rate = 88.8% (95% CI: 82.5–93.5%) and FP/c = 2.7).ConclusionsRetina U-Nets are a valuable tool for tumor detection tasks on PET/CT and can form the backbone of reading assistance tools in this field. FPs have anatomical correlates that can lead the way to further algorithm improvements. The code is publicly available.Key Points• Detection of malignant lesions in PET/CT with Retina U-Net is feasible.• All false-positive findings had anatomical correlates, physiological bone marrow activity being the most prevalent.• Retina U-Nets can build the backbone for tools assisting imaging professionals in lung tumor staging.Supplementary InformationThe online version contains supplementary material available at 10.1007/s00330-022-09332-y.