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Fas-associated death domain (FADD) upregulation, i.e., gene amplification, protein phosphorylation and/or overexpression, has shown promising prognostic implications in head and neck squamous cell carcinoma (HNSCC). This systematic review and meta-analysis aims to evaluate the clinicopathological and prognostic significance of FADD upregulation in HNSCC. We searched studies published before February 2020 through PubMed, Embase, Web of Science, Scopus and Google Scholar. We evaluated the quality of the studies included using the QUIPS tool. The impact of FADD upregulation on survival and clinicopathological variables was meta-analysed. We explored heterogeneity and their sources, conducted sensitivity analyses and investigated small-study effects. Thirteen studies (1,923 patients) met inclusion criteria. FADD immunohistochemical overexpression was statistically associated with worse overall survival (hazard ratio [HR] = 1.52, 95% confidence intervals [CI] = 1.28–1.81, p < 0.001), disease-specific survival (HR = 2.52, 95% CI = 1.61–3.96, p < 0.001), disease-free survival (HR = 1.67, 95% CI=1.29–2.15, p < 0.001), higher clinical stage (odds ratio [OR] = 1.72, 95% CI = 1.17–2.51, p = 0.005) and a large magnitude of effect with N+ status (OR = 2.36, 95% CI = 1.85–3.00, p < 0.001). FADD phosphorylation in ser-194 demonstrated no prognostic value, while no conclusive results can be drawn for FADD gene amplification. In conclusion, our findings indicate that immunohistochemical assessment of FADD overexpression could be incorporated into the prognostic evaluation of HNSCC. [ABSTRACT FROM AUTHOR]