Background and Objectives Chemokine receptors are involved in tumor progression and several of these receptors, including CXCR3, are expressed by chronic lymphocytic leukemia (CLL) B cells. This study was aimed to examine a possible relationship between CXCR3 expression in CLL and the clinical evolution of the disease. Design and Methods Using flow activated cell sorting (FACS), we analyzed the level of expression of CXCR3 on blood CLL B cells from 76 consecutive patients. The results were correlated with CD38 expression, IgV H gene status and clinical outcome. Results CXCR3, measured as mean fluorescence intensity (MFI), was unimodally expressed by blood tumor cells at various levels (range, 3.5 to 232.3) but levels within individual patients were remarkably stable over time. Low CXCR3 expression by CLL B cells was strongly associated with Rai disease stages III and IV (p< 0.0001) and a pattern of diffuse tumor infiltration of the bone marrow (p< 0.0001). In the 28 cases available for genetic studies, low CXCR3 expression also showed good concordance with tumor unmutated IgV H gene status (p< 0.04), and tended to correlate with high CD38 expression (p< 0.06). Patients with low CXCR3 expression (MFI≤ 15) had a shorter survival (p< 0.0001) and, in multivariate analysis, low CXCR3 expression (MFI≤ 15) was an independent predictor of poor outcome (hazard ratio 24.5; p< 0.01). Interpretation and Conclusions CXCR3 expression by CLL B cells appears to be stable within individual patients. Tests to assay this chemokine receptor are cheap and easy to perform and the results could be of prognostic value in CLL.