Purpose Systemic therapy choice for patients with recurrent and/or metastatic head and neck cancer (R/M HNC) is a challenge. Not much is known about systemic therapies used in daily clinical routine and their outcome. Methods Data of all 283 patients with R/M HNC (89.4% male, median age: 60 years) registered for first-line systemic therapy between 2015 and 2018 in the cancer registries of Thuringia, a federal state in Germany, were included. Patient characteristics and treatment patterns were summarized. Exploratory univariate and multivariate analyses were conducted on select of systemic therapy and prognostic factors for overall survival. Results The most frequent first-line regimens were platinum-based combinations (71.4%), mainly cetuximab + platinum + 5-fluorouracil (32.5%). 32.5, 13.1, 4.9, and 1.1%, respectively, received, a second, third, fourth, and fifth line of systemic therapy. Median follow-up was 5.5 months. Median real-world overall survival was 16.8 months [95% confidence interval (CI) 11.1–22.6]. Alcohol drinking [hazard ratio (HR) 2.375, CI 1.471–3.831; p < 0.001], no second-line therapy (HR 3.425, CI 2.082–5.635, p < 0.001), and application of three agents compared to one agent in first-line therapy (HR 2.798, CI 1.374–5.697; p = 0.005) were associated to decreased overall survival after start of first-line systemic therapy. Termination of second-line treatment because of deterioration of the general condition was the only independent negative prognostic factor (HR 4.202, CI 1.091–16.129; p = 0.037) after start of second-line systemic therapy. Conclusions This study offers useful information, mainly prior to the availability of immunotherapy, on patient characteristics, treatment patterns, and survival in a German real-world population.