Unmanipulated early growth response-1 (Egr-1)-deficient −/− mice have similar heart-to-body weight ratios but express lower amounts of atrial natriuretic factor (ANF), β-myosin heavy chain (β-MHC), skeletal actin, NGF1-A binding protein (NAB)-2, Sp1, c-fos, c-jun, GATA-4, and Nkx2.5 than +/+ or +/− mice. α-MHC, tubulin, and NAB-1 expression was similar. Isoproterenol (Iso) and phenylephrine (PE) infusion into +/+ and −/− mice increased heart weight, ANF, β-MHC, skeletal actin, Sp1, NAB-2, c-fos, and c-jun expression, but induction in −/− mice was lower. Only Iso + PE-treated +/+ mice showed induction of NAB-1, GATA-4, and Nkx2.5. Foci of fibrosis were found in Iso + PE-treated −/− and +/+ mice. Surprisingly, vehicle-treated −/− mice displayed fibrosis and increased Sp1, skeletal actin, Nkx2.5, and GATA-4 expression without hypertrophy. Minipump removal caused the agonist-treated hearts and gene expression to regress to control or near-control levels. Thus Egr-1 deficiency caused a blunted catecholamine-induced hypertrophy response and increased sensitivity to stress.