Vascular endothelial growth factor (VEGF) and its receptor family including VEGFR-1 (Fit-1) were recently shown to be involved in pathological angiogenesis including tumor angiogenesis, tumor metastases, inflam-matory disease such as rheumatoid arthritis, psoriasis, and atherosclerosis. Rheumatoid arthritis (RA) is a chronic systemic disease characterized by an inflammatory erosive synovicitis and a pannus of inflammatory vascular tissue, leading to irreversible cartilage and bone destruction. A few cytokines such as TNF-α, IL-1 and IL-6 are known to be involved in RA. VEGF-A was reported to be highly expressed in synovial fluid in human RA, suggesting a role in RA progression. We have recently shown that VEGFR-1 is expressed not only in vascular endothelial cells but also in inflammatory cells, especially in monocyte/macrophage. However, the molecular basis of their actions on RA is not fully understood. Here we report that in a murine model of RA, deletion of the tyrosine kinase (TK) domain of VEGFR-1 (Vegfr-1 tk-/-) decreased the incidence and clinical symptoms of RA. Pathological symptoms, such as synovial hyperplasia, inflammatory infiltrates, pannus formation and cartilage/bone destruction became milder in Vegfr-1 tk-/- mice compared with Wild-type (Wt) mice in the Human T-cell Leukemia Virus-1 pX (HTLV-1 pX) induced chronic models. VEGFR-1 TK-deficient bone marrow cells showed a suppression of multi-lineage colony formation. Furthermore, macrophages induced to differentiate in vitro showed a decrease in phagocytosis and the secretion of Interleukin-6 (IL-6) and VEGF-A. Treatment of this RA model with a small molecule inhibitor for VEGFR TK, KRN951, also attenuated the arthritis. These results indicate that the VEGFR-1 TK signaling modulates the proliferation of bone marrow hematopoietic cells and immunity of monocyte/macrophages, and promotes chronic inflammation, which may be a new target in the treatment of RA.