OBJECTIVES: Functional imaging with positron emission tomography (PET) is a promising non-invasive modality in the clinical management of squamous cell carcinoma of the head and neck (SCCHN). Currently, there is limited evidence that points to the potential cost-effectiveness of PET in this setting. The objective of this study was to assess the methodological quality of cost-effectiveness analyses (CEAs) of PET in SCCHN. METHODS: A systematic literature review was performed focusing on CEAs of PET in SCCHN using MEDLINE, EMBASE, NHS EED and the CEA Registry. Studies were screened according to a priori eligibility criteria. The methodological quality of the primary clinical studies was examined by QUality Assessment of Diagnostic Accuracy Studies checklist. CEAs were critically appraised using the Drummond checklist. RESULTS: A total of seven studies met the inclusion criteria. PET or computed tomography (CT) integrated with PET was assessed in two indications: detection of recurrent disease and screening for metastasis. In each indication, PET strategy ranged from likely to be cost-effective (in four studies) to likely to be cost-saving (in three studies). Prevalence of disease, diagnostic accuracy and cost of PET were the most influential variables. Ranges for sensitivity, specificity and the cost of PET were 53%-100%, 82%-95% and €787-€1,225, respectively. Sources of bias in the diagnostic accuracy studies were mainly related to the representative patient population and interpretation of the index test and reference case. Critical assessment of the CEAs revealed that issues of documentation, feasibility of adopting PET in daily practice and generalizability were key areas that affected quality. CONCLUSIONS: PET, as a reliable diagnostic tool, has the potential to improve disease detection and avoid futile procedures that can lead to morbidity and high costs. Given the limitations of the existing studies, future CEAs should prospectively explore the expanding applications and cost-effectiveness of PET in SCCHN.