Malignant cells are capable of influencing the microenvironment in a manner that facilitates tumor cell survival. Bidirectional crosstalk between chronic lymphocytic leukemic (CLL) cells and marrow-derived mesenchymal stromal cells (MSCs) activates both cell types. In this study, we observed that the conditioned medium (CM) obtained from CLL cells was able to induce Akt activation in MSC. Subsequent studies investigated the mechanism of MSC activation mediated by CLL-CM. Platelet-derived growth factor receptors (PDGFRs) were selectively activated in MSCs by CLL-CM and found to be critical receptors for CLL-CM-driven MSC proliferation and MSC Akt activation. The known ligands of PDGFR, platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF), were detected in CLL-CM, but PDGF was the predominant ligand involved in the CM-mediated PDGFR activation. Both PDGF and VEGF were found to be elevated in the plasma of CLL patients with a positive association for high-risk factors and more advanced stage. Finally, we demonstrated that PDGF induced MSC VEGF production through a phosphatidylinositol 3-kinase (PI3K)-dependent mechanism. These results show that PDGF-PDGFR signaling influences at least the MSC in the microenvironment of CLL and may play a role in the induction of an angiogenic switch known to be permissive for disease progression.