Background: In France, there were an estimated 18.000 incident lymphoma cases in 2018. Currently, most of the knowledge comes from clinical trials (CT), with stringent inclusion criteria and poor representativeness. Real world data (RWD) is essential to complement CT data, but major challenges such as feasibility and data quality remain. In this context, the REal world dAta in LYmphoma and Survival in Adults (REALYSA) multicentric prospective cohort started in 2018 (NCT03869619), with a recruitment objective of 6000 patients and a 9-year follow-up (FU). Aims: The aims of this study are (i) to evaluate the capacity of a real-world program to provide high-quality data that translate into meaningful clinical endpoints, and (ii) to describe the demographic and clinical characteristics as well as therapeutic management and treatment effectiveness of 1st line (1L) DLBCL patients. Methods: Patients diagnosed with 7 histological lymphoma subtypes are included in REALYSA at diagnosis after signing informed consent. Patients receive standard routine care. Data collection includes demographic, clinical, quality of life and epidemiological data at inclusion and every 6 to 12 months. A biobank is also constituted. A strong data validation system inspired from clinical research standards, including care pathway visualisation tools, is regularly running. Meaningful real-life endpoints were derived, such as end of treatment (EoT) evaluation and event-free survival (EFS). We present here the results of a proof-of-concept analysis for REALYSA patients with a DLBCL diagnosis and who received a 1L treatment. Results: Thirty-five hospitals/clinics are currently participating to REALYSA across France. As of Jan 31st 2022, 1217 patients with DLBCL were included in REALYSA with a mean number of 60 patients per month; 645 epidemiological questionnaires were collected; and there were more than 1500 samples in the biobank. The analysis was conducted on 645 DLBCL patients included in REALYSA before March 31st 2021. Median age was 66.3 years [54-75]. Most patients were male (344; 53.3%), with advanced-stage disease (Ann-Arbor stage III/IV for 472 patients (73.3%)), extra-nodal locations (499; 77.4%) and elevated LDH level (402; 64.0%). The international prognostic index was 2 to 5 for 486 patients (76.2%). Treatments received at 1L were R-CHOP (482; 74.7%), R-miniCHOP (86; 13.3%), high dose anthracycline-based regimen (62; 9.6%) and non-anthracycline based regimen (15; 2.3%). Among patients with EoT evaluation done (603), 483 (80.1%) had a complete response, 51 (8.5%) a partial response, 7 (1.2%) a stable disease and 62 (10.3%) a progressive disease. Of note, EoT evaluation was performed by PET/scan for 92% of patients. Median FU was 9.9 months [4.5-17.2]. Results for effectiveness at 12 months were: (i) EFS of 77.9% [95% CI 73.8-81.4]; (ii) PFS of 79.7% [75.6-83.1]; and (iii) overall survival of 90.0% [86.5-92.5]. With the limitation of the short FU, and using backward stepwise regression model, we confirmed that EFS was associated with age, ECOG PS, LDH level and bulk disease. Summary/Conclusion: This analysis showed that REALYSA, the first nationwide real-life cohort on lymphoma, is able to provide high-quality data, with results for 1L DLBCL patients consistent with the literature, including recent phase 3 trials. These data will be useful for numerous purposes, including a better characterization of lymphoma population in France (clinic, epidemiology, biology), as well as innovative study designs (e.g. new outcome endpoints, synthetic control arm).