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Two-thirds of hypopharyngeal squamous cell carcinoma (HPSCC) cases are diagnosed at advanced stages, with the worst prognosis among head and neck squamous cell carcinomas (HNSCCs). We studied 103 Chinese HPSCC patients, finding higher prevalence and poorer prognosis in males. Estrogen response pathways and proteins phosphorylated by PKC and CDKs are aberrantly regulated. Key copy number regions in tumours include <i>SOX2, FGFR, CCND1, CDKN2A/2B</i>, and <i>MYC</i>. HPV status and highly mutated genes like SYNE1 (HPV-) and <i>MUC4 </i>(HPV+) were predictive markers. A predictive model with clinical factors and six gene expressions was validated. This study offers new opportunities for personalized treatment.