I n noncontractile cells, increases in intracellular Ca²⁺ concentration serve as a second messenger to signal proliferation, differentiation, metabolism, motility, and cell death. Many of these Ca²⁺-dependent regulatory processes operate in cardiomyocytes, although it remains unclear how Ca²⁺ serves as a second messenger given the high Ca²⁺ concentrations that control contraction. T-type Ca²⁺ channels are reexpressed in adult ventricular myocytes during pathologic hypertrophy, although their physiologic function remains unknown. Here we generated cardiac-specific transgenic mice with inducible expression of α1G, which generates Ca_v3.1 current, to investigate whether this type of Ca²⁺ influx mechanism regulates the cardiac hypertrophic response. Unexpectedly, α1G transgenic mice showed no cardiac pathology despite large increases in Ca²⁺ influx, and they were even partially resistant to pressure overload–, isoproterenol-, and exercise-induced cardiac hypertrophy. Conversely, α1G^–/– mice displayed enhanced hypertrophic responses following pressure overload or isoproterenol infusion. Enhanced hypertrophy and disease in α1G^–/– mice was rescued with the α1G transgene, demonstrating a myocyte-autonomous requirement of α1G for protection. Mechanistically, α1G interacted with NOS3, which augmented cGMP-dependent protein kinase type I activity in α1G transgenic hearts after pressure overload. Further, the anti-hypertrophic effect of α1G overexpression was abrogated by a NOS3 inhibitor and by crossing the mice onto the Nos3^–/– background. Thus, cardiac α1G reexpression and its associated pool of T-type Ca²⁺ antagonize cardiac hypertrophy through a NOS3-dependent signaling mechanism.