OBJECTIVES: The objective of this systematic literature review (SLR) combined with expert clinical review was to identify and rank prognostic factors and effect measure modifiers (EMMs) systematically and comprehensively in patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) who initiate treatment after ≥ 2 prior lines of therapy (LoTs; 3L+ R/R DLBCL). METHODS: We performed an SLR of studies published between 2016 and 2021 and extracted study characteristics, prognostic factors, and EMMs. This was followed by clinical review and ranking of findings by subject matter experts using questionnaires, follow-up interviews, and quantitative ranking. RESULTS: Across 46 included studies, the SLR identified 36 prognostic factors significantly associated with ≥ 1 clinical outcome. Based on subject matter expert ranking of the SLR-derived list, the five most important prognostic variables in descending order are: early chemo-immunotherapy failure, Eastern Cooperative Oncology Group performance status, refractory to last LoT, number of prior LoTs, and double- or triple-hit lymphoma. CONCLUSIONS: This SLR and expert clinical review is the first to provide a comprehensive assessment of prognostic factors for 3L+ R/R DLBCL. No statistically significant EMMs were identified. This robust multi-method approach can assist in selecting prognostic variables for comparative analyses between real-world studies and clinical trials.