Abstract: Abnormal proliferation of vascular smooth muscle cells (VSMCs) plays an important role in several pathological processes of cardiovascular diseases. In this study, the effects of XCT790, a potent and selective inverse agonist of estrogen-related receptor α (ERRα), on rat VSMCs proliferation and related signal pathways were investigated. The proliferative activity of VSMCs was determined by CCK-8 assay. The mRNA levels of ERRα, PGC-1α, OPN and MCAD were assayed by RT-PCR. The protein levels of ERRα, ERK2 and p-ERK1/2 were evaluated by Western blotting. ELISA was used to assess the protein expression of VEGF. The results showed that XCT790 (5-20 μmol·L^-1) inhibited rat VSMCs proliferation, and the expression of ERRα and its target genes, as well as p-ERK1/2, were also inhibited. XCT790 inhibited VSMCs proliferation in a dose-dependent manner at the dose range from 5 to 20 μmol·L^-1 and in a time-dependent manner at the dose range from 10 to 20 μmol·L^-1. These findings demonstrate that XCT790 inhibits rat VSMCs proliferation by down-regulating the gene level of ERRα and thus inhibiting the ERK signal pathway, suggesting that ERRα may be a novel potential target for therapeutic approaches to inhibit VSMCs proliferation, which plays an important role in several cardiovascular diseases.