Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma. Despite a high cure rate, too many patients show refractory (ref) or relapsed (rel) disease. This study examines the frequency of recurring gene mutations and their interplay with well-known biomarkers in female and male patients between 18 and 80 years with ref/rel DLBCL compared to patients with complete remission (CR) to identify biological risk factors associated with treatment response, using cohorts of R-CHOP-like treated DLBCL enrolled in clinical trials of the DSHNHL. The biomarker profile of patients differed between younger and elderly patients with ref/rel DLBCL, with a higher frequency of