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). The gene discussed is HSPA5; the disease is oropharynx squamous cell carcinoma.