Background: This retrospective cohort analysis looked at real-world data from Spain to better understand the characteristics, treatment patterns and clinical outcomes of patients with aHNSCC who received immunotherapy in an advanced setting. In aHNSCC, the standard of care was platinum-based chemotherapy. However, this treatment modality is associated with significant toxicity and only a minority of patients achieve long-term disease control. As a result, there was an unmet need for effective and well-tolerated treatment till immunotherapy has shown efficacy in some clinical trials. However, data on the use of immunotherapy in routine clinical practice are limited. The aim of this study was to characterize the real-world safety and effectiveness of immunotherapy in patients with aHNSCC in real practice. Methods: This was a retrospective cohort study that included data from our database, a tertiary hospital in Spain. Patients with a diagnosis of aHNSCC who received immunotherapy between 2017 and 2022 were included, excluding those in clinical trials. Clinical outcomes assessed were overall survival (OS), progression-free survival (PFS), response rate (RR), and toxicity profile. 97 patients were included in the analysis. The most common histological subtype was oral cavity cancer (43%), followed by laryngeal cancer (29%). Results: The majority of patients had stage IVA-B disease at diagnosis (62%). A 53% of patients received first line nivolumab as monotherapy, or pembrolizumab as monotherapy or combined with platinum chemotherapy, and a 58% of patients received second or third line nivolumab as monotherapy.With a median age of 64 years (range: 45-86), most patients received it as second-line or later treatment (70%). The overall response rate was 29%, with durable responses seen in some patients (28% longer than 1 y). The median overall survival was 13.9 months in first-line setting (3-24 mo), and the 1-year survival rate was 36%. In second-line setting, the median OS was 11.1 mo (3-89 mo), and 1-year survival rate was 33%. More frequent toxicities were skin (26%) and endocrine (21%). We had 8 cases of hyperprogressive disease (8.2%) and treatment was interrupted due toxicity in 6 patients. Conclusions: These results are very close to results found in clinical trials (KEYNOTE-048, CheckMate 141) and confirm that immunotherapy is safe and impacts on survival of aHNSCC patients. We need to identify predictive biomarkers for response and toxicity.