Canine DLBCL is highly chemo-sensitive, and dose-intense multidrug chemotherapy may lead to prolonged survival ; however, some DLBCLs do not respond to therapy. Identifying CNAs associated with response to chemotherapy or survival could be beneficial to dogs with a poor prognosis, for which new treatments may be sought. In the present study, oligo aCGH was applied in dogs with DLBCL, by pairing tumoral DNA with normal DNA obtained through skin biopsies. DNA obtained from control tissues within the same subject allowed to find somatogenetic aberrations related to DLBCL, thereby excluding possible polymorphic genomic variations correlated with breed. Overall, aCGH provided a comprehensive high-resolution scanning of the DLBCL genome and identified multiple regions of recurrent copy number Doxorubicin changes, one of which was significantly correlated with a shorter duration of remission. The analysis of the genes located within the chromosomal segments with recurrent alterations in at least two dogs identified a total of 1,363 genes in pre-treatment DLBCLs. A number of known and previously unknown oncogenes were identified, some of which have already been reported to be associated with cancer, including: ADCY8, ZFAT, BAI1, PTK2, FBXL6, FOXH1, HSF1, and UGT2A1. The DAVID analysis, considering genes belonging to gain regions, highlighted numerous molecular pathways significantly enriched. This was mainly due to the recurrent gain of two whole chromosomes, chr13 and chr31 that, even if being attributable to “single events”. Interestingly, the great majority of enriched BP terms was related to nucleotide biosynthesis and IMP metabolism, rate-limiting step for purine synthesis, and therefore playing an important role in the regulation of cell growth and malignancy development. This finding was confirmed also by KEGG analysis, with the most enriched term being Ascorbate and aldarate metabolism, pathway reported to be dis-regulated in breast and ovarian cancer in humans and linked to nucleotide metabolism. The only KEGG term enriched in loss regions was Huntington’s disease, represented mainly by genes involved in oxydative phosphorylation. This finding is of particular interest if considering that OxPhos deficits have been recently associated with malignancies and tumor growth. When considering only deleted regions, the most significant BP pathway was the Immune response. This was not surprising, given the extremely high frequency of IG heavy and light chain loci deletions detected in cDLBCL that involve both IGK, IGL and IGH. Even if the canine IGH locus is minimally annotated, comparison with human orthologous genes locates the canine IGH locus in CFA 8q33, a region frequently found to be deleted in cDLBCL. The loss of IGK in pre-treatment DLBCLs was found in all cases, and the same region was also identified in the three relapsed DLBCLs and in the lymph nodes of two dogs that were in remission at the end of therapy.