Population-based studies on early mortality in head and neck cancer (HNC) are sparse. This retrospective population-based study investigated early mortality of HNC and the influence of patients’ tumor and treatment characteristics. All 8288 patients with primary HNC of the German federal state Thuringia from 1996 to 2016 were included. Univariate and multivariate analysis were performed to identify independent factors for 30-day, 90-day, and 180-day mortality. The 30-, 90-, and 180-day mortality risks were 1.8%, 5.1%, and 9.6%, respectively. In multivariable analysis, male sex (odds ratio (OR) 1.41; 95% confidence interval (CI) 1.08–1.84), increasing age (OR 1.81; CI 1.49–2.19), higher T (T4: OR 3.09; CI 1.96–4.88) and M1 classification (OR 1.97; CI 1.43–2.73), advanced stage (IV: OR 3.97; CI 1.97–8.00), tumors of the cavity of mouth (OR 3.47; CI 1.23–9.75), oropharynx (OR 3.01; CI 1.06–8.51), and hypopharynx (OR 3.27; CI 1.14–9.40) had a significantly greater 180-day mortality. Surgery (OR 0.51; CI 0.36–0.73), radiotherapy (OR 0.37; CI 0.25–0.53), and multimodal therapy (OR 0.10; CI 0.07–0.13) were associated with decreased 180-day mortality. Typical factors associated with worse overall survival had the most important impact on early mortality in a population-based setting.