The prevalence of left ventricular hypertrophy (LVH) is frequent in patients with end-stage renal disease following chronic renal failure (CRF). We investigated the therapeutic efficacy of curcumin, the principal curcuminoid of the Indian curry spice turmeric, in attenuation of LVH and sought to delineate the associated signaling pathways in blunting the hypertrophic response in nephrectomized rats. Adult Sprague-Dawley rats underwent nephrectomy (Nx) by removal of 5/6 of the kidneys. Four groups were studied for 7 wk: 1) control (sham), 2) Nx, 3) Nx + curcumin (150 mg/kg bid), and 4) Nx + enalapril (15 mg/kg bid) as positive control. Subtotal nephrectomy caused renal dysfunction, as evidenced by a gradual increase in proteinuria and elevation in blood urea nitrogen and plasma creatinine. Nx rats showed a significant hypertrophic response and increased diameter of inferior vena cava at inspiration, which was inhibited by treatment with curcumin or enalapril. Moreover, the Nx rats demonstrated changes in the signaling molecules critically involved in the hypertrophic response. These include increased glycogen synthase kinase-3β phosphorylation, β-catenin expression, calcineurin, phosphorylated (p) nuclear factor of activated T cells, pERK, and p-cAMP-dependent kinase. Both curcumin and enalapril variably but effectively deactivated these pathways. Curcumin attenuates cardiac hypertrophy and remodeling in nephrectomized rats through deactivation of multiple hypertrophic signaling pathways. Considering the safety of curcumin, these studies should facilitate future clinical trials in suppressing hypertrophy in patients with CRF.