Introduction: We aimed at investigating the prognostic role of the neutrophil-to-lymphocyte ratio (NLR) in 2 independent cohorts of Latin American patients with diffuse large B-cell lymphoma (DLBCL) treated with chemoimmunotherapy. Patients and Methods: The learning cohort was composed of 274 patients and the validation cohort of 323 patients, for a total of 597 patients. An optimal NLR cutoff ≥ 4 was determined using receiver operating characteristic analysis. Results: In multivariate models, NLR ≥ 4 was independently associated with lower odds for complete response to chemoimmunotherapy in the learning (odds ratio, 0.46; P =.006) and the validation cohort (odds ratio, 0.49; P =.01), and independently associated with worse survival in the learning (hazard ratio, 1.55; P =.04) and the validation cohort (hazard ratio, 1.80; P =.003). Conclusions: The adverse prognostic value of NLR ≥ 4 was independent of the International Prognostic Index and the National Comprehensive Cancer Network-International Prognostic Index score. Based on the results of this multi-institutional study, NLR ≥ 4 emerges as an adverse prognostic factor in Latin American patients with DLBCL treated with chemoimmunotherapy.