A significant increase in intracellular Ca2+ is required to trigger the remodeling of the cell plasma membrane. Scott syndrome is an extremely rare inherited disorder of the transmembrane migration of phosphatidylserine toward the exoplasmic leaflet in blood cells. We have recently reported a reduced capacitative Ca2+ entry in Scott cells [Martinez et al. (1999) Biochemistry 38, 10092-10098]. We have investigated here the links between defective phosphatidylserine exposure and Ca2+ signaling in Scott cells by focusing on the Ca2+ entry following the emptying of intracellular stores. After depletion of caffeine- or thapsigargin-sensitive stores, Ca2+ entry was lower in Scott compared to control lymphoblasts. However, the simultaneous depletion of both types of stores restored a normal Ca2+ influx across the plasma membrane in Scott cells and phosphatidylserine externalization ability was improved concomitantly with capacitative Ca2+ entry. These observations point to the essential role of capacitative Ca2+ entry in the control of phosphatidylserine exposure of stimulated cells.