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Background: ‘ALARM’ is a systematic review of available literature aiming to provide updated information on the prevalence of Human Papillomavirus (HPV) in locally-regionally advanced (LA) and recurrent/metastatic (RM) head and neck cancer (HNC) worldwide. Methods: Electronic searches were conducted on clinicaltrials.gov, MEDLINE (via Pubmed), Embase and ASCO/ESMO journals of congresses for interventional studies (IS; phase I-III trials) as well as MEDLINE and Embase for non-interventional studies (NIS) of LA/RM HNC published between 01Jan2010 and 31Dec2020. Criteria for study selection included: availability of HPV prevalence data for patients with LA/RM HNC, patient enrollment from 01Jan2010 onwards, and oropharyngeal cancer (OPC) included among HNC types. HPV prevalence per study was calculated as proportion of HPV-positive (HPV+) over total number of HNC enrolled patients. For overall HPV prevalence across studies, mean of reported HPV prevalence rates across studies and pooled estimate, i.e., sum of all HPV+ patients over sum of all HNC patients enrolled, were assessed. Results: Eighty-one studies (62 IS; 19 NIS) were included in this evidence synthesis, representing 9607 LA/RM HNC cases, with an overall mean (pooled) HPV prevalence of 32.6% (25.1%). HPV prevalence was 44.7% (44.0%) in LA and 24.3% (18.6%) in RM. Among 2714 LA/RM OPC patients from 52 studies with available data, the mean (pooled) value was 55.8% (50.7%). The majority of published HPV prevalence data were derived from countries in Northern America and Europe, with overall HPV prevalence of 46.0% (42.1%) and 24.7% (25.3%) across studies conducted exclusively in these geographic regions, respectively. Mean (pooled) HPV prevalence in Northern Europe was 31.9% (63.1%), numerically higher than the European average. A “p16-based” assay was the most frequently reported HPV detection methodology (58.0%). Conclusion: Over the last decade, at least one quarter of LA/RM HNC and half of OPC cases studied in IS and NIS were HPV+, with variation across disease stages and geographic regions. This alarming burden is consistent with a potential implication of HPV in the pathogenesis of at least a subgroup of HNC. The observed rates underscore the relevance of HPV testing and prophylaxis to the prevention and management of these cancers. PROSPERO Number: CRD42021256876