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Background and Objectives The chromosome 13 deletion (Δ13) is one of the most frequent chromosomal alterations in multiple myeloma (MM). Δ13 is associated with an unfavorable prognosis, although there is increasing agreement that its prognostic relevance must be related to the ploidy status and the presence of different chromosomal translocations. The aim of this study was to provide a comprehensive analysis of the transcriptional features of Δ13 in MM.Design and Methods Highly purified plasma cells from 80 newly diagnosed MM patients were characterized by means of fluorescence in situ hybridization (FISH) and high-density oligonucleotide microarray for gene expression profiling and chromosomal alterations.Results We identified 67 differentially expressed genes in the patients with and without the chromosome 13 deletion, all of which were downregulated in the cases with Δ13: 44 mapped along the whole chromosome 13, seven on chromosome 11 and three on chromosome 19. Functional analyses of the selected genes indicated their involvement in protein biosynthesis, ubiquitination and transcriptional regulation. An integrative genomic approach based on regional analyses of the gene expression data identified distinct chromosomal regions whose global expression modulation could differentiate Δ13-positive cases, in particular the upregulation of 1q21-1q42 and the downregulation of 19p and almost the entire chromosome 11. FISH analyses confirmed the close relationship between Δ13-positivity and the presence of extra copies of 1q21-1q42 (p=6 × 10−4) or the absence of chromosome 11 and 19 trisomy (p=5 × 10−4).Interpretation and Conclusions Our results indicate that distinct types of chromosomal aberrations are closely related to the transcriptional profiles of Δ13-positive cases, suggesting that the contribution of Δ13 to the malignancy should be considered together with associated abnormalities.