SDF-1α and its receptor CXCR4 are involved in multiple myeloma (MM) by attracting and activating plasma cells in the bone marrow. CXCR4 expression in MM cells is inversely correlated with disease activity. The aim of this study was to evaluate CXCR4 as a prognostic tool in MM, as well as other markers of disease, such as chromosomal aberrancies. Purpose was to investigate the expression levels of SDF-1α before and after bortezomib and thalidomide treatment. From February 2006 to April 2012, CXCR4 expression was prospectively assessed in bone marrow samples from a large population of patients (n=227) using flow cytometry. Clinical characteristics were collected and chromosomal aberrancies were assessed in 144 patients. SDF-1α levels were determined using ELISA in peripheral blood samples from 40 patients before and after chemotherapy. Our results show that CXCR4 was present in 43.2% (98/227) of newly diagnosed MM patients and that CXCR4 expression was significantly correlated with CD117 (P<0.05). CXCR4-positive MM patients had a significantly longer estimated survival time than CXCR4-negative patients (median of 48 vs. 42 months, P<0.05). Multivariate survival analyses identified that the +1q21/CXCR4- phenotype is an independent survival predictor, along with the International Staging System (ISS) stage. No significant difference was observed in expression levels of SDF-1α before and after bortezomib/thalidomide treatment. In conclusion, +1q21/CXCR4- could be an independent survival prognosis predictor in MM patients. Expression levels of SDF-1α before and after bortezomib/thalidomide treatment are not different, although they are higher than in controls.