Inflammation is a key event in hypertensive organ damage, and TNF-alpha and IL-1 beta are elevated in hypertension. In this study, we evaluated the effects of TNF-alpha and IL-1 beta elevation on hypertensive cardiac damage by treatment with a bifunctional inflammatory inhibitor, TNF receptor 2-fragment crystalization-IL-1 receptor antagonist (TFI), which can neutralize these 2 cytokines simultaneously. A mouse hypertension model of angiotensin II (Ang II) infusion (1500 ng/kg.min for 7 d) was induced in wild-type mice. TNF-alpha and IL-1 beta were inhibited by TFI administration (5 mg/kg, every other day), the effects of inhibition on cardiac damage were examined, and its mechanism on inflammatory infiltration was further studied in vivo and in vitro. Ang II infusion induced cardiac injury, including increased macrophage infiltration, expression of inflammatory cytokines (IL-12, IL-6, etc), and cardiac fibrosis, such as elevated alpha-smooth muscle actin, collagen I, and TGF-beta expression. Importantly, the Ang II-induced cardiac injury was suppressed by TFI treatment. Moreover, TFI reduced the expression of adhesion molecules (intercellular adhesion molecule-1 and vascular cell adhesion molecule-1) and monocyte chemotactic protein-1 expression in Ang II-treated hearts. Additionally, blockade of TNF-alpha and IL-1 beta by TFI reduced monocyte adherence to endothelia cell and macrophage migration. This study demonstrates that blocking TNF-alpha and IL-1 beta by TFI prevents cardiac damage in response to Ang II, and targeting these 2 cytokines simultaneously might be a novel tool to treat hypertensive heart injury.