Background: Isolated regional recurrences following head-neck squamous-cell carcinomas (HNSCC) are often accessible for curatively intended salvage treatment. Factors prognostic for outcome were investigated in a large cohort of HNSCC patients. Methods: In total, 1811 patients receiving curatively intended radiotherapy from 2007 to 2017 were reviewed and isolated cervical nodal recurrences were identified. Factors associated with survival and second recurrence were investigated using univariate and multivariate analyses. Results: Isolated regional recurrence was seen in 95/1811 (5.2%) patients. Eighty of 95 patients (84%) received salvage surgery. Two-year survival after isolated regional recurrence was 40%. Overall survival (OS) and time to second recurrence were associated with resection status of the salvage surgery and presence of extranodal spread (ENS), while p16-positive oropharyngeal squamous-cell carcinoma (OPSCC) was associated with better OS. Conclusion: Long-term survival after regional recurrence in HNSCC is possible. p16-positive OPSCC, complete salvage surgery, and lack of ENS are associated with better outcome.