The absolute monocyte/lymphocyte count prognostic score (AMC/ALC score) has not been directly compared with the cell of origin (COO) to predict overall survival (OS) and progression-free survival (PFS) in diffuse large B-cell lymphoma (DLBCL). Thus, we retrospectively examined a new cohort of 99 patients with DLBCL treated from 2008 to 2010, (1) to validate whether AMC/ALC score affects survival, (2) to investigate whether AMC/ALC score is independent of COO to predict survival and (3) to assess whether AMC/ALC score can further stratify clinical outcomes by COO. By univariate analysis, the AMC/ALC score was a predictor for OS and PFS. On multivariate analysis performed including the COO and the International Prognostic Index, AMC/ALC score remained an independent predictor for OS and PFS. The AMC/ALC score was able to further stratify DLBCL clinical outcomes by COO. The AMC/ALC score was independent of COO and added to its ability to identify patients with high-risk disease.