Recently, classical banding cytogenetic studies suggested that follicular lymphomas (FLs) grade 3 with preserved maturation to centrocytes (FL3A) are closely related to FL grades 1 and 2 and frequently harbor the t(14;18), whereas FL grade 3B, consisting of centroblasts exclusively, do frequently show 3q27 alterations. To clarify the prevalence of BCL6 and BCL2 rearrangements in FL and diffuse large B-cell lymphomas (DLBLs), we performed a large scale bicolor interphase cytogenetic (fluorescence in situ hybridization) study on 188 well-characterized B-NHLs classified according to the World Health Organization Classification of Tumors of the Lymphoid Tissues. BCL6 rearrangements were detected in a significantly higher number of FL3B with a DLBL component (12 of 22, 55%) compared with purely diffuse nodal DLBLs (19 of 77, 25%) and DLBLs with a well-documented primary extranodal origin (2 of 27, 7%) (P < 0.001). Five FL3B without a DLBL component were negative for both t(14;18) and 3q27 aberrations. FL grades 1/2 and FL3A were t(14;18)-positive in 88% and 64% of cases, respectively, but 3q27 alterations were identified in only four FL3A. These data exemplify different genetic pathways in the genesis of FLs with a high content of centroblasts and suggest that 3q27 rearrangements are predominantly associated with FL grade 3B harboring a DLBL component.