The present study showed that silencing EGFR increased radiosensitivity of both radiosensitive and radioresistant oropharyngeal squamous cell carcinoma (OSCC) cells by inhibiting ER stress signaling (PERK‐eIF2α‐GRP94 and IRE1α‐XBP1‐GRP78). This evidence concerns the gene EIF2AK3 and oropharynx squamous cell carcinoma.