Introduction: Diffuse large B-cell lymphoma (DLBCL) is the most common type of B-cell lymphoma, predominantly afflicting older adults. There remains a notable absence of data regarding DLBCL in older adults in Latin America. Materials and Methods: We conducted a retrospective analysis of 608 newly diagnosed Latin American patients with DLBCL aged ≥65 years. Results: The median age at diagnosis was 74 years (range: 65–96 years), 51 % were female, 36 % had an Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≥2, and 65 % had advanced disease. The most common regimens used were standard-dose R-CHOP (n = 420, 69 %), R-CVP (n = 77, 12 %), R-mini-CHOP (n = 74, 12 %), and CHOP/CVP (n = 30, 5 %). With a median follow-up of 60 months (95 % confidence interval [CI]: 38.7–75.2 months), the five-year overall survival (OS) rate was 50 % (95 % CI, 43–58). An ECOG PS ≥2 (hazard ratio [HR] 1.93; 95 % CI 1.51–2.46; p < 0.01), advanced clinical stage (HR 1.46; 95 % CI 1.12–1.91; p < 0.01), increased serum lactic dehydrogenase level (HR 1.48; 95 % CI 1.16–1.87; p < 0.01), and albumin level < 3.5 mg/dL (HR 1.64; 95 % CI 1.29–2.10; p < 0.01) were associated with an inferior OS. Using anthracyclines (HR 0.50; 95 % CI 0.38–0.66; p < 0.01) and using rituximab (HR 0.51; 95 % CI 0.36–0.73; p < 0.01) were independently associated with a superior OS. Discussion: In a large cohort of Latin American older patients with DLBCL, therapy and outcome patterns are similar to those reported internationally. The lack of standardized geriatric assessments in Latin America represents an essential area for research to better stratify older patients with DLBCL deemed to be at higher risk for toxicity.