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Background: Nebivolol is a β-adrenergic receptor antagonist that has intrinsic activity on β3-adrenergic receptors (β3-ARs). Previous studies suggest that nebivolol inhibits bFGF-induced vascular smooth muscle cell (VSMC) proliferation and migration and vascular injury-induced neointima formation through activation of β3-ARs. However, our recently published data shown that activation of β3-ARs produced the opposite results, suggesting that the mechanisms of nebivolol-mediated effects are not fully understood. The current project was to study the mechanisms of nebivolol’s effects on bFGF-induced VSMC proliferation and migration by comparing to the selective β3-AR agonist, CL316,243. Methods: VSMCs isolated from Sprague Dawley rat aortas were pretreated with nebivolol or CL316,243 followed by stimulation with bFGF. Cell proliferation and migration and phosphorylation of ERK and AKT were measured. Results: We found that pretreatment of VSMCs with nebivolol produced biphasic effects on bFGF-induced VSMC proliferation, manifested as potentiation at lower concentrations and inhibition at the higher concentration. The effects of low concentrations of nebivolol on bFGF-induced VSMC proliferation was blocked by the selective β3-AR antagonist, SR59230A. Nebivolol inhibited bFGF-induced cell migration at all concentrations tested. In addition, only higher concentrations of nebivolol significantly inhibited bFGF-induced AKT phosphorylation but not ERK phosphorylation whereas CL316,243 at all concentrations tested significantly enhanced bFGF-induced VSMC proliferation and migration and higher concentrations of CL316,243 not only enhanced bFGF-induced AKT phosphorylation but also ERK phosphorylation. Conclusion: Our data suggest that the effect of nebivolol on bFGF-induced cell proliferation is concentration-dependent. The enhancement on bFGF-induced cell proliferation at lower concentrations appears to be mainly mediated by activation of β3-ARs but the inhibitory effects on bFGF-mediated cell proliferation as well as migration may occur through different mechanisms. AKT signaling is only involved in high concentrations of nebivolol-mediated effects.