BACKGROUND: This study aimed to assess the impact of prior treatment status on isolated regional recurrence (IRR) of head and neck squamous cell carcinoma (HNSCC). METHODS: Total 159 IRR cases after definitive treatment for HNSCC were enrolled. Patients without initial neck treatment were classified into the non-treated group (N = 42), while those who underwent initial neck treatment were classified into the treated group (N = 117). RESULTS: The distinct differences in 5-year recurrence-free survival (RFS) and overall survival (OS) after salvage treatment rates were identified, with 78.6% and 78.6% in the previously non-treated group and 41.0% and 47.9% in the treated group. In multivariable analysis, initial T4 and N3 stages, advanced recurred N stage, and prior neck treatment status at salvage were factors predicting adverse salvage treatment outcomes. CONCLUSION: Our findings demonstrate poorer oncologic outcomes of IRR salvage treatment rates in previously treated fields of isolated neck recurrence of HNSCC than in non-treated fields, with distinct differences in RFS and OS.