A rise in cytosolic Ca²⁺ concentration ([Ca²⁺]_cyt) due to Ca²⁺ release from intracellular Ca²⁺ stores and Ca²⁺ influx through plasmalemmal Ca²⁺ channels plays a critical role in mitogen-mediated cell growth. Depletion of intracellular Ca²⁺ stores triggers capacitative Ca²⁺ entry (CCE), a mechanism involved in maintaining Ca²⁺ influx and refilling intracellular Ca²⁺ stores. Transient receptor potential (TRP) genes have been demonstrated to encode the store-operated Ca²⁺ channels that are activated by Ca²⁺ store depletion. In this study, we examined whether CCE, activity of store-operated Ca²⁺ channels, and humanTRP1 (hTRP1) expression are essential in human pulmonary arterial smooth muscle cell (PASMC) proliferation. Chelation of extracellular Ca²⁺ and depletion of intracellularly stored Ca²⁺ inhibited PASMC growth in media containing serum and growth factors. Resting [Ca²⁺]_cyt as well as the increases in [Ca²⁺]_cyt due to Ca²⁺ release and CCE were all significantly greater in proliferating PASMC than in growth-arrested cells. Consistently, whole cell inward currents activated by depletion of intracellular Ca²⁺ stores and the mRNA level of hTRP1 were much greater in proliferating PASMC than in growth-arrested cells. These results suggest that elevated [Ca²⁺]_cyt and intracellularly stored [Ca²⁺] play an important role in pulmonary vascular smooth muscle cell growth. CCE, potentially viahTRP1-encoded Ca²⁺-permeable channels, may be an important mechanism required to maintain the elevated [Ca²⁺]_cyt and stored [Ca²⁺] in human PASMC during proliferation.