Waldenstrom Macroglobulinemia (WM) is a B-cell malignancy characterized by excess bone marrow (BM) lymphoplasmacytic cells (LPC). The accumulation of LPC in WM may represent a failure of B-cells to properly differentiate into plasma cells. The present study investigated transcriptional expression of genes involved in late B-cell differentiation, including PRDM1, PAX5, XBP1 transcripts and ERN1, in BM B-cells from 31 patients with WM and six healthy donors. Real time reverse transcription polymerase chain reaction (RT-PCR) determined that approximately 80% of the patients had high XBP1 spliced mRNA expression, 80% of whom had high mRNA ERN1alpha expression. XBP1, PRDM1 and PAX5 mRNA was present in all patients studied. Using relative quantitative RT-PCR we isolated two groups with low and high expression of XBP1, XBP1 spliced and ERN1alpha. Sequence analysis showed germline polymorphisms in all genes studied. These data depict for the first time a heterogeneous expression pattern of the genes involved in late differentiation process of plasma cells in patients with WM and propose a role of XBP1-ERN1alpha in WM pathogenesis.