Background: Aldosterone (Aldo) is a key regulator of blood pressure and electrolyte balance. Aldo/salt has been shown to induce oxidative stress, inflammation, cardiac hypertrophy and fibrosis. TRAF3 interacting protein 2 (TRAF3IP2) is a cytoplasmic redox-sensitive adaptor molecule and an upstream regulator of NF-κB and AP-1. It plays a critical role in the regulation of various proinflammatory cytokines that exert prohypertrophic and profibrotic effects. Therefore, we hypothesized that TRAF3IP2 is a critical mediator of Aldo/salt-induced cardiac hypertrophy and fibrosis. Methods: TRAF3IP2-null and wild type (WT) mice (male, 12-13 weeks) were infused continuously with Aldo for 4 weeks via mini-osmotic pumps (0.2 mg/Kg/day; n = 6-8). Mice were fed 1% NaCl in drinking water. Salt alone served as control. Systolic blood pressure (SBP) was measured by tail-cuff plethysmography, myocardial function by echocardiography, cardiac hypertrophy by heart weight to body weight ratios, cardiac fibrosis by trichrome Gomori, and gene and protein expression by RT-qPCR, immunoblotting and ELISA. Results: Aldo/salt elevated SBP to a similar extent in both TRAF3IP2-null and WT mice. Aldo/salt upregulated TRAF3IP2 expression in left ventricular homogenates from WT mice, and TRAF3IP2 gene deletion (vs. WT) blunted cardiac hypertrophy by 54% (p < 0.05), suppressed ANP expression by 3.5 fold (p < 0.05), prevented concentric LV remodeling (decreased LVPWs; 93%; p < 0.01, LVPWd; 95%; p < 0.05, LVAWs; 29.8%; p < 0.05 and LVAWd; 26.2%, and increased LVIDs; 19.2%; p < 0.01 and LVIDd; 8.53%) and markedly reduced both interstitial and perivascular fibrosis. Further, TRAF3IP2 gene deletion inhibited Aldo/salt-induced p65 and c-Jun activation, and expression of inflammatory cytokine (IL-18 and IL-6), matrix metalloproteinase (MMP2) and extracellular matrix proteins (collagen Iα1 and IIIα1). TRAF3IP2 gene deletion also blunted mRNA and protein expression of lysyl oxidase, an enzyme involved in collagen crosslinking. Conclusions: TRAF3IP2 gene deletion blunts Aldo/salt-induced cardiac hypertrophy and fibrosis by inhibiting proinflammatory, prohypertrophic, and profibrotic effects, signifying its potential as a therapeutic target in hypertrophic heart diseases.