Incidence of isolated distant metastasis (IDM) was relatively low in patients who achieved locoregional control after primary definitive surgery. However, the prognosis of patients with IDM was dismal. The aim of this study was to evaluate the clinical outcome of patients with IDM and identify independent predictive factors of IDM after primary definitive surgery for head and neck squamous cell carcinoma (HNSCC). A retrospective data review was conducted for 795 patients who underwent primary definitive surgery without any systemic treatment for squamous cell carcinoma (SCC) of the oral cavity, oropharynx, larynx, and hypopharynx. Distant metastasis-free survival was calculated and independent predictive factors for IDM were determined by Cox proportional-hazards model. For the entire study cohort, IDM developed in 75 patients (9.4%). Among 631 patients who achieved locoregional control, IDM occurred in 44 patients (7%). The median time to IDM after primary surgery was 13months, ranging from 2 to 70months. The overall salvage rate was 9% (4 of 44) after salvage treatment for IDM. In the Cox proportional-hazards model, clinical N status, and histological grade were independent predictive factors of IDM. Patients who had clinically palpable neck disease and a histologically poor grade were more likely to develop IDM after primary definitive surgery. Patients with these factors should be considered candidates for proper adjuvant systemic treatment and evaluated more thoroughly for early detection of IDM during follow-up.