Fewer than half of patients with diffuse large B-cell lymphoma (DLBCL) can be cured. Molecular prognostic factors in the rituximab era must be re-evaluated, because there are few molecular indicators with prognostic value. Samples of DLBCL from 41 newly diagnosed patients with a median follow-up of 52 months were studied. Immunohistochemical staining was performed to investigate the expression of apoptosis-related proteins (Bcl-2 and caspase 3a), cell proliferation (Ki-67), and tumor microenvironmental factors. Two groups were analysed, 23 cases (56%) treated with CHOP and 18 (44%) treated with R-CHOP. Survival analysis showed that cases with overexpression of Bcl-2 had worse overall survival (OS) in the CHOP group. However, OS in the R-CHOP group was adversely affected by lack of caspase 3a staining. In the entire series, cases positive for caspase 3a showed significantly better OS, without significance for other parameters, and caspase 3 was associated with parameters of prognosis and OS in R-CHOP. This is the first study that relates caspase 3a and prognosis in DLBCL.