Myelomatous plasma cells (PC) show a high heterogeneity both in their immunophenotypic characteristics as well as in their cytogenetic features. So far, no extensive studies have been carried out to explore whether such antigenic diversity is associated with specific genetic characteristics. We have investigated the relationship between the immunophenotypic profile at PC and both their DNA ploidy status (evaluated by flow cytometry), and specific genetic features (ascertained by FISH) in a large series of 915 patients with newly diagnosed MM. The non-hyperdiploid MM group (n=454, 52%) was associated with a significantly higher frequency of positivity for CD28 and CD20 as well as a higher incidence of CD56− and CD117− cases (p<0.001). Remarkably, 13q deletion and IGH gen rearrangements, which were significantly more common in non-hyperdiploid MM, showed a strong association with CD117- cases. IGH translocation to 11q13 was associated with reactivity for CD20 (p<0.001), down-regulation of CD56 (p<0.001) and lack of expression of CD117 (p=0.001). By contrast, IGH translocations to other chromosome partners were almost exclusively found among CD20− and CD117− cases (p<0.001). These results suggest that genetic categories in MM exhibit a particular immunophenotypic profiles which in turn are strongly associated with the DNA ploidy status.