Diffuse large B-cell lymphoma (DLBCL) is the most frequent entity among non-Hodgkin lymphoma (NHL). It is a clinically and biologically heterogeneous disease regarding treatment response and long-term outcome. The anthracycline-based regimen R-CHOP is still considered as the standard of care for first-line treatment allowing achieving a complete response for approximately 60% of the patients. The prognosis of patients with primary refractory or relapsed (R/R) disease is particularly poor with a median overall survival below one year. Only a fraction of R/R patients can be cured with salvage therapies due to the acquisition of chemoresistance. We conducted a large-scale and deep proteomic investigation of the proteome profiles of R/R DLBCL patients compared to chemosensitive patients in order to identify new potential biomarkers related to resistance to treatment and to better understand the biological mechanisms underlying chemoresistance.