The role of protein kinase C (PKC) and their isoforms in cell growth regulation remains elusive. Here we showed that in cultured human vascular smooth muscle cells (SMC), the PKC stimulator phorbol 12-myristate 13-acetate (PMA) inhibited [H-3]thymidine incorporation in response to the growth factor PDGF associated with downregulation of PDGF beta (but not alpha) receptors, which was recovered to normal level after PKC was depleted. The changes in PDGF beta receptor were inversely correlated with PKC beta1 protein levels regulated by PMA. The downregulation of PDGF beta receptor by PMA was fully prevented by the PKC beta inhibitor LY379196, however, without recovery of [H-3]thymidine incorporation to PDGF. In contrast, [H-3]thymidine incorporation was fully recovered after depletion of PKCs. These results indicate that in human SMC PKC beta1 mediates PDGF beta receptor downregulation. Other PKC isoforms activated by phorbol ester also contribute to the inhibitory effects on cell growth.