A fast-track pathway has been established in Denmark to investigate patients with serious nonspecific symptoms and signs of cancer (NSSC), who are not eligible to enter an organ-specific cancer program. The prevalence of cancer in this cohort is approximately 20%. The optimal screening strategy in patients with NSSC remains unknown. The aim of the study was to investigate whether 18 F-FDG PET/CT was superior to CT as an initial imaging modality in patients with NSSC. In a randomized prospective trial, the imaging modalities were compared with regard to diagnostic performance. Methods: Two hundred patients were randomized 1:1 to whole-body 18 F-FDG PET/CT or CT of the thorax and abdomen as the imaging modality. A tentative diagnosis was established after first-line imaging. The final referral diagnosis was adjudicated by the physician, when sufficient data were available. Results: One hundred ninety-seven patients were available for analysis because 3 patients withdrew consent before scanning. Thirty-nine (20%) patients were diagnosed with cancer, 10 (5%) with an infection, 15 (8%) with an autoimmune disease, and 76 (39%) with other diseases. In the remaining 57 patients (28%), no specific disease was found. 18 F-FDG PET/CT had a higher specificity (96% vs. 85%; P 5 0.028) and a higher accuracy (94% vs. 82%; P 5 0.017) than CT. However, there were no statistically significant differences in sensitivity (83% vs. 70%) or negative predictive values (96% vs. 92%). No difference in days to final referral diagnosis according to randomization group could be shown (7.2 vs. 7.6 d). However, for the subgroups in which the imaging modality showed a suggestion of malignancy, there was a significant delay to final diagnosis in the CT group compared with the 18 F-FDG PET/CT group (11.6 vs. 5.7 d; P 5 0.02). Conclusion: Compared with CT, we found a higher diagnostic specificity and accuracy of 18 F-FDG PET/CT for detecting cancer in patients with NSSC. 18 F-FDG PET/CT should therefore be considered as first-line imaging in this group of patients. In2009,f ast-track cancer patient pathways were introduced by the Danish Health and Medicine Authority for patients with nonspecific symptoms and signs of cancer (NSSC) in Denmark. The background for the implementation was that Danish patients experience poorer cancer survival rates than patients from other European countries and were diagnosed with an unfavorable delay (1-4). Since 2012, Diagnostic Outpatient Clinics (DOC) have been established in the Capital Region of Denmark for patients with NSSC because early diagnosis in cancer is of importance for a more favorable outcome (5-8). The criterion for referral to DOC was a suspicion from the referring physicians, in more than 95% of the cases the patient's general practitioner, that the patient had an NSSC. The referral was typically prompted by one or more of the following observations: increasing health service-seeking behavior; weight loss; tiredness; or a group of unspecific symptoms, which did not fit into any of the organ-speci...