Different smooth muscle cell phenotypes coexist in arteries. The majority of cells cultured from a normal rat aortic media have a spindle-shaped phenotype while cells isolated from an intimal thickening 15 days after endothelial injury show a distinct epithelioid phenotype. These two phenotypes express their own specific set of genes and differ in their proliferation and migration characteristics. We studied growth factor-induced DNA synthesis in both phenotypes and investigated the potential mechanisms behind the differences in growth characteristics. Insulin-like growth factor-I (IGF-I), platelet-derived growth factor (PDGF-BB), and basic fibroblast growth factor (FGF) increased thymidine incorporation in both phenotypes, but the increase was markedly stronger in neointimal cells than in medial cells. Northern blot analysis 30 min after growth factor stimulation showed that c-FOS and c-JUN mRNAs were induced more strongly in neointimal than in medial cells. IGF-I receptor and PDGF-R beta levels were higher in neointimal cells than in medial cells, but the FGF receptor level was not different between the cell types. In summary, our results indicate that neointimal cells are more sensitive to growth factors than medial cells, likely due to a higher expression of IGF-I receptor and PDGF-R beta. Our results provide insight into the mechanism by which epithelioid cells play a primary role in vascular neointima formation.