Multiple myeloma (MM) is a progressive B-lineage neoplasia characterized by the accumulation of slow proliferative malignant plasma cells in the bone marrow compartment where the microenvironment seems to be favorable for their growth and survival. Heparan sulfate proteoglycans such as syndecan-1 and CD44 are thought to play a central role in the survival signals provided by these bone marrow survival niches, which require complex interactions between myeloma cells, extracellular matrix, stromal cells and soluble factors. In this report, we demonstrate that interleukin-6 (IL-6), the main survival and growth factor for myeloma cells, strongly increases CD44 gene expression. In addition, we show that IL-6 modulates CD44 RNA alternative splicing and induces the overexpression of all CD44 variant exons. Finally, we show that IL-6-induced CD44 cell surface molecules have a functional polarized membrane distribution. As IL-6 secretion induced from bone marrow stromal cells by myeloma cells is partly mediated through direct cell-to-cell interaction involving CD44 adhesion molecules, our findings suggest that a CD44/IL-6 amplification loop plays a crucial role in myeloma cell survival.