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Salvage surgery for recurrent oral squamous cell carcinoma (OSCC) often leads to a poor quality of life (QOL). The present study described three cases that resulted in favorable locoregional control with cetuximab in combination with radiotherapy (Cmab+RT). Case1 had regional recurrence of OSCC at the lower right mastoid area 4months after primary surgery. Case2 had regional recurrence of OSCC at the parotid area 7months after primary surgery. Case3 had local recurrence of OSCC at the masticatory muscle and Rouviere's lymph nodes 1year and 3months after primary surgery. In all cases, Cmab+RT was performed, and disease‑free survival was confirmed 4months, 2years and 6months, and 10months after Cmab+RT, respectively. Immunohistochemically, all resected tumors had no expression of 110‑kDa catalytic subunit of class IA phosphatidylinositol 3‑kinase (PI3Kp110α). In conclusion, if salvage surgery for recurrent OSCC results in a significantly low QOL, then shifting to chemoradiotherapy may be appropriate as a treatment strategy. In addition, strong evidence indicated that PI3Kp110α expression is associated with Cmab therapy efficacy., Oncology Letters, 24(6), art. no. 431; 2022