Primary central nervous system lymphomas (PCNSLs) are germinal center-derived diffuse large B-cell lymphomas (DLBCLs) arising in and remaining confined to the brain, the pathogenesis of which is poorly understood. We investigated 13 PCNSLs from immunocompetent patients by means of interphase cytogenetics on cryopreserved cells derived from stereotactic biopsies. Interphase fluorescence in situ hybridization (FISH) was performed for the detection of structural alterations affecting the IGH (14q32), IGK (2p12), IGL (22q11), BCL6 (3q27), MYC (8q24), CCND1 (11q13), MLT, and BCL2 (both 18q21) loci. Signal constellations indicating breakpoints within the IGH and IGK locus were detected in 5 and 1 PCNSLs, respectively. There was no evidence for a t(8;14), t(11;14), or t(14;18) in this series of tumors. Breakpoints in the BCL6 locus were observed in 3 of the 13 cases, and nuclear Bcl-6 protein expression was detected in 6 of 9 PCNSLs, including those with genomic alterations of the encoding locus. Gains of 18q21 represented the most frequent imbalances present in more than one third of all cases. Interestingly, these gains included the MLT gene. Thus, this study provides the first evidence for recurrent chromosomal translocations in PCNSLs. While they share similarities with extracerebral DLBCL with respect to the presence of IGH translocations, they appear to differ in the usage of translocation partner genes, which remain to be identified.