Objective Inflammation contributes to hypertension-induced cardiac damage and fibrotic remodeling. Complement activation produces anaphylatoxins, which are major inflammatory effectors. Here, we investigated the role of complement anaphylatoxins in angiotensin II (Ang II)-induced cardiac remodeling. Approach and Results We measured human plasma levels of complement anaphylatoxins in hypertensive individuals and controls and studied the role of complement activation in a mouse model of Ang II-induced hypertension and cardiac injury. We found that complement 5a (C5a) concentration was more elevated in hypertensive individuals than in controls. Infusion of Ang II in mice for 7 days led to increased anaphylatoxin concentration in plasma and perivascular C3b deposition in the heart. C5a receptor (C5aR)-deficient but not C3a receptor-deficient mice exhibited markedly reduced cardiac remodeling and inflammation after Ang II infusion. Pharmacological inhibition of C5a production by an anti-C5 monoclonal antibody produced similar effects to C5aR deficiency. Bone marrow chimera experiments revealed that C5aR expression on bone marrow-derived cells was critical in mediating Ang II-induced cardiac injury and remodeling. The C5aR pathway regulated the expression of adhesion molecules on peripheral monocytes, as well as infiltration and cytokine production of macrophage in the heart. Conclusions Complement is activated in hypertensive hearts, and the C5aR signaling pathway on blood monocytes/macrophages plays a pathological role in Ang II-induced cardiac inflammation and remodeling. Therapeutic inhibition of complement may protect patients from hypertension-related heart injury.