Waldenström macroglobulinemia (WM) (symptomatic and indolent) and immunoglobulin M (IgM) monoclonal gammopathy of undetermined significance (IgMMGUS) can be identified based on the bone marrow (BM) infiltration and the existence of symptoms. The purpose of this study was to investigate the biological and genetic characteristics of both disorders comparing the molecular signature of WM versus IgMMGUS using microarray analysis. We investigated BM CD19+ cells isolated from 21 WM patients and 10 IgMMGUS cases, and CD138+ BM cells isolated from all of the WM patients and 4 of the IgMMGUS cases. Gene expression profiling of WM versus IgMMGUS CD19+ cells highlighted 151 differently expressed genes and the comparison with CD138+ cells demonstrated 43 differently expressed genes in WM versus IgMMGUS. Regulation of transcription, Janus kinase/signal transducer and activator of transcription, PI3K/Akt/mammalian target of rapamycin, mitogen-activated protein kinase signaling pathways are the relevant gene ontology biological processes occurring in CD19+ cells, and immune response, cell activation, and signaling processes developing in CD138+ cells mainly distinguish WM and IgMMGUS.