Background: The inflammatory response plays a critical role in hypertension-induced cardiac remodeling. We aimed to study how interaction among inflammatory cells causes inflammatory responses in the process of hypertensive cardiac fibrosis. Methodology/Principal Findings: Infusion of angiotensin II (Ang II, 1500 ng/kg/min) in mice rapidly induced the expression of interferon gamma (IFN-gamma) and leukocytes infiltration into the heart. To determine the role of IFN-gamma on cardiac inflammation and remodeling, both wild-type (WT) and IFN-gamma-knockout (KO) mice were infused Ang II for 7 days, and were found an equal blood pressure increase. However, knockout of IFN-gamma prevented Ang II-induced: 1) infiltration of macrophages and T cells into cardiac tissue; 2) expression of tumor necrosis factor a and monocyte chemoattractant protein 1 (MCP-1), and 3) cardiac fibrosis, including the expression of alpha-smooth muscle actin and collagen I (all p<0.05). Cultured T cells or macrophages alone expressed very low level of IFN-gamma, however, co-culture of T cells and macrophages increased IFN-gamma expression by 19.860.95 folds ( vs. WT macrophage, p<0.001) and 20.9 +/- 2.09 folds (vs. WT T cells, p<0.001). In vitro co-culture studies using T cells and macrophages from WT or IFN-gamma KO mice demonstrated that T cells were primary source for IFN-gamma production. Co-culture of WT macrophages with WT T cells, but not with IFN-gamma-knockout T cells, increased IFN-gamma production (p<0.01). Moreover, IFN-gamma produced by T cells amplified MCP-1 expression in macrophages and stimulated macrophage migration. Conclusions/Significance: Reciprocal interaction between macrophages and T cells in heart stimulates IFN-gamma expression, leading to increased MCP-1 expression in macrophages, which results a forward-feed recruitment of macrophages, thus contributing to Ang II-induced cardiac inflammation and fibrosis.