OBJECTIVES: The aim of this study was to investigate the potential benefits and cost consequences of introducing F-Fluorodeoxyglucose Positron Emission Tomography (F-FDG PET) in the diagnostic work-up of patients with suspected recurrent laryngeal cancer after radiotherapy. METHODS: REcurrent LAryngeal carcinoma PET Study (RELAPS), a prospective multicenter randomized controlled trial, recruited 150 patients from eight head and neck cancer centers in the Netherlands and one center in Belgium. Two diagnostic algorithms were compared to the reference standard: (1) Conventional work-up (CWU); direct laryngoscopy with biopsy under general anesthesia, and (2)F-FDG PET work-up (PWU) followed by laryngoscopy; only for positive or equivocal findings. Standard reference comprised histopathology and clinical follow-up of 6- and 12-months, respectively. Diagnostic performance of F-FDG PET and indication of unnecessary operations were efficacy measures. Dutch healthcare perspective was used to obtain input parameters from hospital databases, patient records, literature and publicly available sources. Costs were expressed in 2014 Euros. Sensitivity analysis was performed. RESULTS: Indication for direct laryngoscopy was classified unnecessary in 49 CWU patients (68%, 95%CI: 56-79) compared to 21 PWU patients (28%, 95%CI: 18-40) (p<0.0001). The absolute difference between groups at 12-months was 40%. F-FDG PET had a sensitivity of 96% (95%CI, 78%-100%), specificity of 59% (95%CI, 44%-72%), a positive predictive value of 52% (95%CI, 37%-68%) and a negative predictive value of 97% (95%CI, 83%-100%). Results at 6-months follow-up were similar. Total mean medical costs per patient for PWU and CWU were €11,302 and €11,784 (6-months), and €12,670 and €13,776 (12-months), respectively. The incremental costs were in favor of the PWU patients (€482 (6-months), €1,105 (12-months)). Sensitivity analyses showed that the most influential parameters were hospitalization, treatment-related operations and cost of PET. CONCLUSIONS: The introduction of F-FDG PET in the diagnostic trajectory of laryngeal cancer patients with suspected recurrence after radiotherapy is feasible, safe and favorable from clinical and economic perspectives.