Neuropilin-1 (Npn-1) is a receptor shared by class 3 semaphorins and heparin-binding forms of vascular endothelial growth factor (VEGF), protein families that regulate endothelial and neuronal-cell function. Ligand interaction with Npn-1 dictates the choice of signal transducer; plexins transduce semaphorin signals, and VEGF receptors transduce VEGF signals. It is not clear how class 3 semaphorins affect endothelial-cell function and how the shared receptor Npn-1 selects its ligand. We report that semaphorin3A (Sema3A) inhibits endothelial-cell lamellipodia formation, adhesion, survival, proliferation, and cord formation. VEGF₁₆₅, but not VEGF₁₂₁, could block all these effects of Sema3A. VEGF₁₆₅ competed with Sema3A for binding to endothelial cells, effectively reduced cell-surface Npn-1, and promoted its internalization. Use of soluble forms of Npn-1 or VEGF receptor-1 to block VEGF₁₆₅ binding to Npn-1 or to VEGF receptors provided evidence that surface Npn-1 and VEGF receptors are required for VEGF₁₆₅-induced Npn-1 internalization. Sema3A also reduced cell-surface Npn-1 in endothelial cells and promoted its internalization, but required a higher concentration than VEGF₁₆₅. These results demonstrate that preferential receptor binding and internalization by a ligand are mechanisms by which the common receptor Npn-1 can play an essential role in prioritizing conflicting signals.