Vascular endothelial growth factor (VEGF) signals on vascular and hematopoietic cells via its receptors, VEGFR-2 (KDR) and VEGFR-1 (FLT-1). Elevated levels of VEGF, such as during tumor growth or inflammation, have been suggested to suppress hematopoiesis; most studies refer to KDR as the main receptor involved in this inhibitory effect. In the present study, having detected expression of FLT-1 in B-lymphoid precursors, we exploited the possibility that VEGF signaling via FLT-1 might affect early B-cell commitment. Using a well-established in vitro B-cell differentiation assay, we demonstrate that FLT-1 blockade promotes B-cell commitment and subsequent differentiation, while KDR blockade has no effect on B-cell commitment. In agreement, in vivo transplantation of human (CD34+) or murine (Sca1+l/Lin-) FLT-1-negative hematopoietic precursors into irradiated severe combined immune-deficient mice restored the bone marrow lymphoid compartment, while transplanting the FLT-1-positive counterpart failed to repopulate the lymphoid compartment, and unexpectedly resulted in early death of the irradiated recipients due to hematopoietic suppression. Taken together, we suggest that VEGF signaling via FLT-1 on hematopoietic precursors may restrict lymphopoiesis.