—Cell proliferation and cell death (either necrosis or apoptosis) are key processes in the progression of atherosclerosis. The tumor suppressor gene p53 is an essential gene in cell proliferation and cell death and is upregulated in human atherosclerotic plaques, both in smooth muscle cells and in macrophages. In the present study, we investigated the importance of macrophage p53 in the progression of atherosclerosis using bone marrow transplantation in APOE*3-Leiden transgenic mice, an animal model for human-like atherosclerosis. APOE*3-Leiden mice were lethally irradiated and reconstituted with bone marrow derived from either p53-deficient (p53^−/−) or control (p53^+/+) donor mice. Reconstitution of mice with p53^−/− bone marrow did not result in any hemopoietic abnormalities as compared with p53^+/+ transplanted mice. After 12 weeks on an atherogenic diet, APOE*3-Leiden mice reconstituted with p53^−/− bone marrow showed a significant (P=0.006) 2.3-fold increase in total atherosclerotic lesion area as compared with mice reconstituted with p53^+/+ bone marrow. Although likely a secondary effect of the increased lesion area, p53^−/− transplanted mice also showed significantly more lesion necrosis (necrotic index, 1.1±1.3 versus 0.2±0.7; P=0.04) and lesion macrophages (macrophage area, 79.9±40.0 versus 39.7±27.3×10³ μm² per section; P=0.02). These observations coincided with a tendency toward decreased apoptosis (terminal deoxynucleotidyl transferase end-labeling [TUNEL]–positive nuclei going from 0.42±0.39 to 0.14±0.15%, P=0.071), whereas the number of proliferating cells (5′-bromo-2′-deoxyuridine–positive nuclei) was not affected (3.75±0.98 versus 4.77±2.30%; P=0.59). These studies indicate that macrophage p53 is important in suppressing the progression of atherosclerosis and identify a novel therapeutic target for regulating plaque stability.