The escape of malignant cells from the immune response against the tumor may result from a defective differentiation or function of professional antigen-presenting cells (APC), ie, dendritic cells (DC). To test this hypothesis, the effect of human renal cell carcinoma cell lines (RCC) on the development of DC from CD34⁺progenitors was investigated in vitro. RCC cell lines were found to release soluble factors that inhibit the differentiation of CD34⁺ cells into DC and trigger their commitment towards monocytic cells (CD14⁺CD64⁺CD1a⁻CD86⁻CD80⁻HLA-DR^low) with a potent phagocytic capacity but lacking APC function. RCC CM were found to act on the two distinct subpopulations emerging in the culture at day 6 ([CD14⁺CD1a⁻] and [CD14⁻CD1a⁺]) by inhibiting the differentiation into DC of [CD14⁺CD1a⁻] precursors and blocking the acquisition of APC function of the [CD14⁻CD1a⁺] derived DC. Interleukin-6 (IL-6) and macrophage colony-stimulating factor (M-CSF) were found to be responsible for this phenomenon: antibodies against IL-6 and M-CSF abrogated the inhibitory effects of RCC CM; and recombinant IL-6 and/or M-CSF inhibited the differentiation of DC similarly to RCC CM. The inhibition of DC differentiation by RCC CM was preceeded by an induction of M-CSF receptor (M-CSFR; CD115) and a loss of granulocyte-macrophage colony-stimulating factor receptor  (GM-CSFR; CD116) expression at the surface of CD34⁺cells, two phenomenon reversed by anti–IL-6/IL-6R and anti–M-CSF antibodies, respectively. Finally, a panel of tumor cell lines producing IL-6 and M-CSF induced similar effects. Taken together, the results suggest that the inhibition of DC development could represent a frequent mechanism by which tumor cells will escape immune recognition.