The SH3 domain of PLC-γ1 has been known to induce DNA synthesis. However, little is known about the putative effector proteins that associate with the domain. In this report, we provide evidence that the SH3 domain of PLC-γ1 associates with Shc, which has been implicated in the activation of p21Ras in response to many growth factors. The association between Shc and PLC-γ1 is enhanced either by ν-Src-induced transformation or EGF-stimulation in vivo and in vitro. Furthermore, from transient expression studies with COS-7 cells, we show that the SH3 domain of PLC-γ1 is required for association with Shc in vivo, whereas tyrosyl phosphorylation of PLC-γ1 is not. Taken together, we suggest that Shc might be involved in the PLC-γ1-mediated signaling pathway.