AIM: The progression of atherosclerosis can lead to the occurrence of multiple cardiovascular diseases (coronary heart disease, etc.). E prostanoid receptor-3 (EP3) is known to participate in the progression of atherosclerosis. This study aimed to investigate the mechanism by which EP3 modulates the development of atherosclerosis. METHODS AND RESULTS: ApoE-/- mice were used to construct in vivo model of atherosclerosis. Human aortic smooth muscle cells (HASMCs) were stimulated with oxidized low-density lipoprotein (ox-LDL) to construct in vitro model of atherosclerosis. mRNA expressions were assessed by qRT-PCR, and western blot was applied to assess the protein levels. CCK-8 assay was applied to assess the cell viability. The inflammatory cytokines levels were assessed by enzyme-linked immunosorbent assay, and flow cytometry was applied to assess cell apoptosis. In vivo experiment was constructed to investigate the impact of EP3 in atherosclerosis development. L-798106 (EP3 inhibitor) significantly inhibited the levels of pro-inflammatory cytokines in atherosclerosis in vivo. EP3 inhibitor (L-798106) significantly reversed ox-LDL-caused HASMCs injury via inhibiting the apoptosis and inflammatory responses (P < 0.05). The levels of interleukin-17 (IL-17) and intercellular adhesion molecule-1 (ICAM-1) in HASMCs were elevated by ox-LDL, whereas L-798106 or knockdown of cyclic AMP (cAMP) response element-binding protein (CREB) notably restored this phenomenon (P < 0.05). EP3 overexpression further aggravated ox-LDL-induced inflammation in HASMCs, and EP3 up-regulated the levels of IL-17 and ICAM-1 in ox-LDL-treated HASMCs (P < 0.05). EP3 up-regulation promoted the inflammatory responses in ox-LDL-treated HASMCs through mediation of cAMP/protein kinase A (PKA)/CREB/IL-17/ICAM-1 axis (P < 0.05). CONCLUSIONS: EP3 inhibitor alleviates ox-LDL-induced HASMC inflammation via mediation of cAMP/PKA/CREB/IL-17/ICAM-1 axis. Our study might shed new lights on discovering novel strategies against atherosclerosis.