Cell motility plays a critical role for many physiological and pathological processes including wound healing, fibrosis, angiogenesis, and tumor metastasis. Platelet-derived growth factor (PDGF) is among the most potent stimuli for mesenchymal cell migration. The PDGF B-chain homodimer PDGF BE activates both alpha- and beta -receptor subunits (alpha -PDGFR and beta -PDGFR), and promotes cell migration in many cell types including fibroblasts and smooth muscle cells. PDGF-A chain homodimer PDGF AA activates alpha -PDGFR only, and its role for cell migration is still debatable. PDGF BE, but not PDGF AA, induces smooth muscle cell migration. Interestingly, alpha -PDGFR was shown to antagonize beta -PDGFR-induced smooth muscle cell migration. In the present study, we investigated the role of alpha -PDGFR and beta -PDGFR in PDGF-mediated cell migration of murine fibroblasts (NIH 3T3), Unlike smooth muscle cells, both PDGF AA and PDGF BE promoted NIH 3T3 cell migration. The effect of PDGF BE activation of beta -PDGFR alone for cell migration was examined using previously established NIH 3T3 clones in which alpha -PDGFR signaling is inhibited by a dominant-negative alpha -PDGFR, or an antisense construct of alpha -PDGFR. PDGF BE activation of beta -PDGFR alone was sufficient to induce cell migration, but the efficiency was significantly lower compared to PDGF activation of both receptors, These results showed that both alpha- and beta -PDGFRs promote fibroblast cell migration and their effects are additive. Taken together, we propose that cell-type specific alpha -PDGFR signaling is critical for regulation of mesenchymal cell migration in response to PDGF isoform, whereas beta -PDGFR mainly promotes cell migration.