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Defective dendritic cell (DC) function has been described previously in cancer patients and tumor-bearing mice. It can be an important factor in the escape of tumors from immune system control. However, the mechanism and clinical significance of this phenomenon remain unclear. Here, 93 patients with breast, head and neck, and lung cancer were investigated. The function of peripheral blood and tumor draining lymph node DCs was equally impaired in cancer patients, consistent with a systemic rather than a local effect of tumor on DCs. The number of DCs was dramatically reduced in the peripheral blood of cancer patients. This decrease was associated with the accumulation of cells lacking markers of mature hematopoietic cells. The presence of these immature cells was closely associated with the stage and duration of the disease. Surgical removal of tumor resulted in partial reversal of the observed effects. The presence of immature cells in the peripheral blood of cancer patients was closely associated with an increased plasma level of vascular endothelial growth factor but not interleukin 6, granulocyte macrophage colony-stimulating factor, macrophage colony-stimulating factor, interleukin 10, or transforming growth factor-beta and was decreased in lung cancer patients receiving therapy with antivascular endothelial growth factor antibodies. These data indicate that defective DC function in cancer patients is the result of decreased numbers of competent DCs and the accumulation of immature cells. This effect may have significant clinical implications.