Background: Non-Hodgkin's lymphoma (NHL) represents a major complicationof AIDS. Systemic AIDS-related NHLs (AIDS-NHLs) derive from B cells and areclassified into four distinct groups, including small noncleaved-celllymphoma (SNCCL), diffuse large-cell lymphoma (DLCL), anaplastic large-celllymphoma (ALCL), and body-cavity-based lymphoma (BCBL). The molecularpathogenesis of AIDS-NHL is characterized by the association of specificgenetic lesions with distinct AIDS-NHL categories. Genetic lesions ofAIDS-NHL involve proto-oncogenes (c-myc, Ras), tumor suppressor loci (p53,6q), and viral infection (Epstein–Barr virus, human herpesvirus type8). Design: The aim of this work was to define the involvement of the bcl-6gene in AIDS-related lymphomagenesis by investigating the distribution ofbcl-6 structural alterations throughout the pathologic spectrum of AIDS-NHL.Both gross rearrangements and mutations in the 5′ noncoding regions ofthe gene were investigated. Results: Gross rearrangements of bcl-6 are confined to a fraction ofAIDS-DLCL cases among AIDS-NHLs. Conversely, mutations of the 5′noncoding regions of bcl-6 are detected in a large proportion ofAIDS-SNCCLs, AIDS-DLCLs and AIDS-ALCLs independent of the concomitantpresence of bcl-6 rearrangements. Conclusions: Mutations of the 5′ noncoding regions of bcl-6 represent the most frequent genetic lesion presently detectable amongsystemic AIDS-NHLs. The frequency of these mutations and their location in theproximity of bcl-6 regulatory regions suggest that they may play a rolein AIDS-related lymphomagenesis.