The angiotensin II (AngII) receptor, AT₁, plays a critical role in hypertrophy of vascular smooth muscle cells (VSMCs). Although it is well-known that G_q is the major G protein activated by the AT₁ receptor, the requirement of G_q for AngII-induced VSMC hypertrophy remains unclear. By using cultured VSMCs, this study examines the requirement of G_q for the epidermal growth factor receptor (EGFR) pathway, the Rho-kinase/ROCK pathway, and subsequent hypertrophy. AngII-induced intracellular Ca²⁺ elevation was completely inhibited by a pharmacological G_q inhibitor as well as by adenovirus encoding a G_q inhibitory mini-gene. AngII (100 nM)-induced EGFR transactivation was almost completely inhibited by these inhibitors, whereas these inhibitors only partially inhibited AngII (100 nM)-induced phosphorylation of a ROCK substrate, myosin phosphatase target subunit-1. Stimulation of VSMCs with AngII resulted in an increase of cellular protein and cell volume, but not in cell number. The G_q inhibitors completely blocked these hypertrophic responses, whereas a G protein-independent AT₁ agonist did not stimulate these hypertrophic responses. In conclusion, G_q appears to play a major role in the EGFR pathway, leading to vascular hypertrophy induced by AngII. Vascular G_q seems to be a critical target of intervention against cardiovascular diseases associated with the enhanced renin-angiotensin system.