Tumor-associated macrophages are major infiltrates of human solid malignancies and play an important role in tumor angiogenesis by production of angiogenic factors. In the present study, we examined whether macrophage- melanoma cell interaction regulates vascular endothelial cell growth factor-A (VEGF-A) expression in macrophages. We analyzed the expression of mediators of monocyte recruitment and differentiation, such as monocyte chemotactic protein-1 (MCP-1) and macrophage colony-stimulating factor (M-CSF) in malignant melanoma specimens and tumor cells with different metastatic potential. Our data demonstrate that MCP-1 and M-CSF are differentially expressed in human malignant melanomas from different thickness and depth of invasion and cell lines. Next, we examined the effect of MCP-1 and M-CSF on modulation of VEGFA expression in monocytes/macrophages. Treatment of human monocytes with M-CSF and MCP-1 enhanced VEGF-A expression by increased hypoxia-inducible factor-1alpha (HIF-1alpha) expression and enhanced activation of the hypoxia response element (HRE). Further activation of monocytes and monocyte-derived macrophages (MDM) by lipopolysaccharide (LPS) caused an increase in VEGF-A expression. We demonstrate that coculture of melanoma cells with monocytes enhanced VEGF-A secretion, and conditioned medium from MDMs enhanced melanoma cell expression of VEGF-A. Furthermore, conditioned medium from melanoma cells enhanced VEGF-A expression in human monocytes, which was abrogated by anti-M-CSF neutralizing antibody. In summary, we demonstrate that MCP-1 and M-CSF, critical for monocyte recruitment, activation, and differentiation, differentially regulate VEGF-A expression and may play an important role in monocyte/macrophage- mediated tumor angiogenesis.