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Phospholipase C-γ (PLC-γ) was rapidly phosphorylated on tyrosines and serines following PDGF and EGF treatment of quiescent 3T3 mouse fibroblasts and A431 human epidermoid cells, respectively. PDGF treatment increased PLC-γ phosphorylation within 30 sec. This lasted for up to 1 hr, and occurred at high stoichiometry. Continuous receptor occupancy was required to maintain this phosphorylation. Three major sites of tyrosine phosphorylation were detected in PLC-γ, two of which were phosphorylated in EGF-treated A431 cells. Under certain conditions PDGF receptor coimmunoprecipitated with PLC-γ, suggesting that PDGF receptor can phosphorylate PLC-γ directly. Indeed, purified PDGF or EGF receptor phosphorylated purified PLC-γ on tyrosines identical to those phosphorylated in vivo. Tyrosine phosphorylation of PLC-γ was not induced by bombesin, TPA, or insulin. Stimulation of PLC-γ tyrosine phosphorylation and the reported ability of PDGF and EGF to induce phosphatidylinositol turnover in different cells were strongly correlated. We propose that tyrosine phosphorylation of PLC-γ by PDGF and EGF receptors leads to its activation, and a consequent increase in phosphatidylinositol turnover.