Stimulation of the epidermal growth factor receptor (EGFR) produces membrane ruffles through the small G protein Rac1; however, the signaling pathway from EGFR to Rac1 has not yet been clarified. Here, we show that autophosphorylation of EGFR at tyrosine 992 is required for EGF-induced membrane ruffle formation in CHO cells. Signaling from the autophosphorylated tyrosine 992 appears to be mediated by phospholipase C (PLC) gamma 1. Furthermore, activation of Rac1 by EGF is inhibited by a PLC inhibitor. These results, taken together, suggest that autophosphorylation of EGFR at tyrosine 992 and the subsequent PLC gamma 1 activation transduce the signal to Rac1 to induce membrane ruffle formation.