Background: Immune checkpoint inhibitors (ICIs) are increasingly used to treat several types of tumors. Impact of this emerging therapy on patients’ health-related quality of life (HRQoL) is usually collected in clinical trials through standard questionnaires. However, this might not fully reflect HRQoL of patients under real-world conditions. In parallel, users’ narratives from social media represent a potential new source of research concerning HRQoL. Objective: The aim of this study is to assess and compare coverage of ICI-treated patients’ HRQoL domains and subdomains in standard questionnaires from clinical trials and in real-world setting from social media posts. Methods: A retrospective study was carried out by collecting social media posts in French language written by internet users mentioning their experiences with ICIs between January 2011 and August 2018. Automatic and manual extractions were implemented to create a corpus where domains and subdomains of HRQoL were classified. These annotations were compared with domains covered by 2 standard HRQoL questionnaires, the EORTC QLQ-C30 and the FACT-G. Results: We identified 150 users who described their own experience with ICI (89/150, 59.3%) or that of their relative (61/150, 40.7%), with 137 users (91.3%) reporting at least one HRQoL domain in their social media posts. A total of 8 domains and 42 subdomains of HRQoL were identified: Global health (1 subdomain; 115 patients), Symptoms (13; 76), Emotional state (10; 49), Role (7; 22), Physical activity (4; 13), Professional situation (3; 9), Cognitive state (2; 2), and Social state (2; 2). The QLQ-C30 showed a wider global coverage of social media HRQoL subdomains than the FACT-G, 45% (19/42) and 29% (12/42), respectively. For both QLQ-C30 and FACT-G questionnaires, coverage rates were particularly suboptimal for Symptoms (68/123, 55.3% and 72/123, 58.5%, respectively), Emotional state (7/49, 14% and 24/49, 49%, respectively), and Role (17/22, 77% and 15/22, 68%, respectively). Conclusions: Many patients with cancer are using social media to share their experiences with immunotherapy. Collecting and analyzing their spontaneous narratives are helpful to capture and understand their HRQoL in real-world setting. New measures of HRQoL are needed to provide more in-depth evaluation of Symptoms, Emotional state, and Role among patients with cancer treated with immunotherapy.< Réduire