Loss of major histocompatibility class II (MHC class II) molecules on diffuse large B-cell lymphoma (DLBCL) has been associated with poor survival; however, none of these reports analysed a uniformly treated patient cohort. This study was designed to validate one MHC class II antigen, HLA-DR, as a prognostic marker in patients uniformly treated with the MACOP-B regimen. Immunostaining results were correlated with the international prognostic index (IPI) score and overall survival (OS). Of the 97 cases, 82 had interpretable staining. Of these, 52 expressed HLA-DR (median OS, 16.2 years) while 30 were negative (median OS, 4.2 years, P = 0.037). The IPI was also predictive of OS in the study group (P = 0.023). A Cox multivariate model established both IPI (P = 0.031) and HLA-DR (P = 0.04) as independent predictors of OS. This is the first demonstration of the prognostic relevance of HLA-DR in a uniformly treated DLBCL patient group.