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Abstract Aim  The clinical usefulness of 2-deoxy-2-[F-18]fluoro-D-glucose-positron emission tomography (FDG-PET) in head and neck squamous cell carcinoma (HNSCC) is now well-documented. However, its sensitivity is greater than its specificity due to false-positive results in inflammatory or infectious lesions, which are frequent in this area, in particular after treatment by surgery and/or radiotherapy. O-2-fluoro-(18F)-ethyl-L-thyrosine (FET) has been reported not to be taken up by such lesions, and a preliminary study indicated that this may be clinically useful in HNSCC. We performed a prospective study to compare the diagnostic performances of FDG and FET PET/CT in the different settings of HNSCC. Materials and Methods  Twenty-seven patients (20 men and seven women, aged 48–76, among 30 patients included) and 69 suspected cancer sites are now evaluable on basis of postsurgical histology and/or follow-up greater than 6 months; 15 patients were referred for initial staging and 12 during posttherapy follow-up, a recurrence being suspected in eight of them. FDG and FET PET/CT were performed on two different days, the patient fasting for 6 h, 1 h after injection of 5 MBq/kg of body mass of each radiopharmaceutical. Both PET/CT examinations were blind read more than 6 months after the end of inclusions in a random order for each tracer and with a time interval greater than 1 month between FDG and FET PET/CT blind readings. Results  Overall diagnostic performances, derived from blind reading: FDG PET/CT on a per patient basis: sensitivity 100%, specificity 71%, accuracy 93%; FDG PET/CT on a per site basis: sensitivity 95%, specificity 63%, accuracy 83%; FET PET/CT on a per patient basis: sensitivity 70%, specificity 100%, accuracy 78%; FET PET/CT on a per site basis: sensitivity 64%, specificity 100%, accuracy 78%. At site level, sensitivity was significantly greater with FDG (p p  Conclusion  Although its good specificity was confirmed, FET did not appear to be suited as a first-line PET tracer in HNSCC imaging and cannot replace FDG for staging due to insufficient sensitivity. However, it was useful in a few selected cases to favor a wait and see attitude when a FDG FET− focus was discovered in patients referred for systematic FDG PET during follow-up. In contrast, second primary cancers should not be ruled out if FDG was clearly positive in the lungs or the digestive tract. [ABSTRACT FROM AUTHOR]