Capacitative Ca²⁺ entry (CCE) through store-operated Ca²⁺ (SOC) channels plays an important role in returning Ca²⁺ to the sarcoplasmic reticulum (SR) and regulating cytosolic free Ca²⁺concentration ([Ca²⁺]_cyt). A rise in [Ca²⁺]_cyt and sufficient Ca²⁺ in the SR are required for pulmonary artery smooth muscle cell (PASMC) proliferation. We tested the hypothesis that platelet-derived growth factor (PDGF)-mediated PASMC growth involves upregulation of c-Jun and TRPC6, a transient receptor potential cation channel. In rat PASMC, PDGF (10 ng/ml for 0.5–48 h) phosphorylated signal transducer and activator of transcription (STAT3), increased mRNA and protein levels of c-Jun, and stimulated cell proliferation. PDGF treatment also upregulated TRPC6 expression and augmented CCE, elicited by passive depletion of Ca²⁺ from the SR using cyclopiazonic acid. Furthermore, overexpression of c-Jun stimulated TRPC6 expression and CCE amplitude in PASMC. Downregulation of TRPC6 using an antisense oligonucleotide specifically for human TRPC6 decreased CCE and inhibited PDGF-mediated PASMC proliferation. These results suggest that PDGF-mediated PASMC proliferation is associated with c-Jun/STAT3-induced upregulation of TRPC6 expression. The resultant increase in CCE raises [Ca²⁺]_cyt, facilitates return of Ca²⁺ to the SR, and enhances PASMC growth.