CXCR4 chemokine receptors retain hematopoietic progenitors and leukemia cells within the marrow microenvironment. We prospectively evaluated the prognostic implication of CXCR4 in 90 consecutive patients with acute myelogenous leukemia (AML) by flow cytometry. Patients were divided into groups with low (n = 32), intermediate (n = 26), or high (n = 32) CXCR4 expression, as defined by CXCR4 mean fluorescence intensity ratio thresholds of less than 5, 5 to 10, or more than 10, respectively. We found that low CXCR4 expression on AML cells correlated with a better prognosis, resulting in a longer relapse-free and overall survival of 24.3 ± 2.9 months for low CXCR4-expressing patients, compared with 17.4 ± 3.4 months for intermediate and 12.8 ± 2 months (mean ± SEM) for patients with high expression. In univariate analyses, CXCR4 expression, cytogenetics, white blood cell count, and serum lactate dehydrogenase (LDH) predicted for shorter survival. Multivariate analysis revealed CXCR4 expression and unfavorable cytogenetics as independent prognostic factors. We conclude that CXCR4 expression in AML is an independent prognostic predictor for disease relapse and survival that can rapidly and easily be determined at disease presentation. These findings warrant further investigation into the role of CXCR4 in AML and suggest that CXCR4 should be incorporated into the risk assessment of AML patients.