The interaction of the chemokine CXCL12 with CXCR4 regulates homing of tumoral cells in bone marrow in Waldenstrom macroglobulinemia (WM). We assessed the distribution and the clinical influence of the CXCL12 (-801GA) polymorphism using PCR RFLP in a series of 114 WM patients. CXCL12 (-801AA) genotype was more frequent in WM patients compared with control subjects (p = 0.01). On the other hand, CXCL12 (-801GG) patients had a shorter median survival after initiation of first line therapy than remaining patients (p = 0.01). In conclusion, the CXCL12 (-801GA) polymorphism may either be associated with a high incidence of WM or influence clinical outcome.