Simple Summary: In 2020, there were 880,000 new cases and 440,000 deaths attributed to head and neck cancer worldwide. Nivolumab was approved in 2016 in the United States, and 2017 in the European Union and Canada, for use in patients with recurrent/metastatic squamous cell carcinoma of the head and neck with progressive disease at or within 6 months after platinum-based therapy. This study was conducted to capture the real-world utilization of nivolumab and to assess the impact of treatment on quality of life among affected patients. The retrospective protocol (VOLUME) described the effectiveness of treatment with nivolumab in terms of survival times and response on imaging, while the prospective protocol (VOLUME-PRO) described the health-related quality of life (HRQoL) among patients treated with nivolumab. This study examined the real-world use of nivolumab in patients with recurrent/metastatic squamous cell carcinoma of the head and neck (R/M SCCHN). This was a multinational retrospective study (VOLUME) assessing treatment effectiveness and safety outcomes and a prospective study (VOLUME-PRO) assessing HRQoL and patient-reported symptoms. There were 447 and 51 patients in VOLUME and VOLUME-PRO, respectively. Across both studies, the median age was 64.0 years, 80.9% were male, and 52.6% were former smokers. Clinical outcomes of interest included real-world overall survival (rwOS) and real-world progression-free survival (rwPFS). The median rwOS was 9.2 months. Among patients with at least one assessment, 21.7% reported their best response as 'partial response', with 3.9% reporting 'complete response'. The median duration of response (DoR) and median rwPFS were 11.0 months and 3.9 months, respectively. At baseline, VOLUME-PRO patients reported difficulties relating to fatigue, physical and sexual functioning, dyspnea, nausea, sticky saliva, dry mouth, pain/discomfort, mobility, and financial difficulties. There were improvements in social functioning and financial difficulties throughout the study; however, no other clinically meaningful changes were noted. No new safety concerns were identified. This real-world, multinational, multicenter, retrospective and prospective study supports the effectiveness and safety of nivolumab for R/M SCCHN patients. [ABSTRACT FROM AUTHOR]