Protein phosphatase 2A (PP2A), a crucial serine/threonine phosphatase, has recently been reported to play an important role in cardiovascular disease. Previous studies have hinted that PP2A is involved in atherosclerosis formation, but the associated mechanisms remain poorly understood. In this study, we investigate the role of PP2A in the pathogenesis of atherosclerosis. In human atherosclerotic coronary arteries, we found that the expression and activity of PP2A decreased significantly when compared to non-atherosclerotic arteries. Additional experiments demonstrated that pharmacological inhibition of PP2A aggravated atherosclerosis of ApoE mice. Considering the central role of macrophages in atherosclerosis, mice with conditional knockout of the PP2A-Cα subunit in myeloid cells were produced to investigate the function of PP2A in macrophages. Results showed that PP2A deficiency in myeloid cells aggravated atherosclerotic lesions in mice. experiments indicated that PP2A-deficient macrophages had an enhanced ability of lipid uptake and foam cell formation. Mechanistically, the deficiency of the PP2A in macrophages led to an increase in the phosphorylation level of p38, which contributed to the elevated expression of scavenger receptor CD36, a key factor involved in lipoprotein uptake. Our data suggest that PP2A participates in the pathophysiological process of atherosclerosis. The decrease of PP2A expression and activity in macrophages is a crucial determinant for foam cell formation and the initiation of atherosclerosis. Our study may provide a potential novel approach for the treatment of atherosclerosis.