ABSTRACT Chromosomal translocations involving the immunoglobulin loci represent frequent oncogenic events in B-cell lymphoma development. Although IRF8 (ICSBP-1) protein expression has been demonstrated in germinal centre B-cells and related lymphomas in a single report, the IRF8 gene was not described as an IGH translocation partner. In a discovery driven approach we searched for new translocation partners of the IGH in DLBCL by long distance inverse (LDI) PCR and Sanger sequencing. A t(14;16)(q32.33;q24.1) IGH/IRF8 was detected in a CD5+ de novo DLBCL, confirmed by translocation specific PCR and FISH analysis. No further IRF8 aberration could be identified neither by LDI-PCR in additional five CD5+ DLBCL nor by FISH on 78 FFPE biopsies. Subsequent screening for IRF8 by immunohistochemistry revealed IRF8 expression in 18/78 (23%) correlating with a GCB type of DLBCL. This hitherto unknown translocation t(14;16)(q32.33;q24.1) is alike to represent the initiator of a multistep lymphomagenesis in a CD5+ de novo DLBCL.