Diffuse large B-cell lymphoma (DLBCL) is an aggressive disease influenced by several genetic and environmental factors. The key role of the Human Leukocyte Antigen (HLA) system in tumor antigen presentation could be involved in susceptibility and disease control. We have analyzed the phenotypic frequencies of HLA-A, -B, -C, -DRB1 and -DQB1 in 250 DLBCLs, comparing them with 1940 healthy individuals. We also evaluated the influence of HLA polymorphisms on survival in those patients treated with curative intention using CHOP-like without (n=64, 26%) or with Rituximab (n=153, 61%). Our data reveal that DLBCL patients have a higher phenotypic frequency of HLA-DRB1*01 (29% vs. 19.5%, P=0.0008, Pc=0.0104) and a lower frequency of HLA-C*03 (6.4% vs. 17.9%, P<0.0005, Pc=0.007) compared with healthy individuals. Irrespective of the aaIPI, those patients receiving a CHOP-like plus Rituximab regimen and carrying the HLA B44-supertype had worse 5-year PFS (54% vs. 71%, P=0.019), and 5-year OS (71% vs. 92%, P=0.001), compared with patients without this supertype. Our data suggest that some HLA polymorphisms influence the development and outcome of DLBCL, allowing the identification of an extremely good-risk prognostic subgroup. However, these results are preliminary and need to be validated in order to exclude a possible population effect.