Background: Nivolumab has demonstrated efficacy in clinical trials of recurrent or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN). As only limited real-world data are available, we describe the use of nivolumab and its outcomes in routine clinical practice. Methods: HANNA is a prospective, observational study of patients with R/M SCCHN treated with nivolumab in 56 hospitals and practices in Germany. In total, 385 patients will be followed for ≤ 5 years from treatment initiation until death, withdrawal of consent, loss of follow-up/record, or end of study. The primary objective is overall survival (OS). Secondary objectives include baseline characteristics, safety profiles, and quality of life (QOL) assessment. Results: By November 2019, data from 311 patients were available. Median follow-up was 3.5 months. Baseline characteristics were male, 81.7%; median age, 63 years; history of smoking, 73.3%; Eastern Cooperative Oncology Group performance status (ECOG PS) 0/1, 60.8%; ECOG PS 2/3, 29.6%. Location of primary tumor was oropharynx, 38.3%; hypopharynx, 20.9%; oral cavity, 22.8%; larynx, 11.6%; others, 6.4%. 55.6% of R/M SCCHN patients progressed ≤ 6 months after platinum-based therapy, whereas 43.4% were platinum-sensitive (progressed > 6 months after platinum-based therapy). Nivolumab was received by 25.1% of patients as first therapy after platinum-based chemo- or radiochemotherapy, by 62.1% as second therapy, and by 12.9% as later line therapy. Median treatment duration was 4.6 months. OS at 1 year was 43.3%. 1-year OS for patients with ECOG PS 0 was 75.9%; ECOG PS 1, 41.2%; and ECOG PS 2, 27.3%. Platinum-sensitive patients had higher 1-year OS probability (51.6%). Drug-related adverse events (grade 1/2) and serious adverse events (grade 3/4) were observed in 28.9% and 10.0% of patients, respectively. Interim QOL data (per FACT-H&N and EQ-5D questionnaire) indicated a tendency toward stabilization or slight improvement. We will present an update of the data with longer follow-up (data cut March 2020). Conclusions: HANNA represents one of the largest real-world datasets for nivolumab in R/M SCCHN and comprises a more diverse set of patients than the phase 3 CheckMate 141 trial, including patients with higher ECOG PS, age, and platinum sensitivity. Outcomes from HANNA show that the improved OS, safety, and QOL seen with nivolumab in the real-world setting are consistent with the outcomes from CheckMate 141. Clinical trial information: NCT03114163.