Calcium (Ca2+) is a critical cofactor and signaling mediator in cells, and the concentration of cytosolic Ca2+ is regulated by multiple proteins, including the plasma membrane Ca2+-ATPases (adenosine triphosphatases) (PMCAs), which use ATP to transport Ca2+ out of cells. PMCA isoforms exhibit different kinetic and regulatory properties; thus, the presence and relative abundance of individual isoforms may help shape Ca2+ transients and cellular responses. We studied the effects of three PMCA isoforms (PMCA4a, PMCA4b, and PMCA2b) on Ca2+ transients elicited by conditions that trigger store-operated Ca2+ entry (SOCE) and that blocked Ca2+ uptake into the endoplasmic reticulum in HeLa cells, human embryonic kidney (HEK) 293 cells, or primary endothelial cell isolated from human umbilical cord veins (HUVECs). The slowly activating PMCA4b isoform produced long-lasting Ca2+ oscillations in response to SOCE. The fast-activating isoforms PMCA2b and PMCA4a produced different effects. PMCA2b resulted in rapid and highly PMCA abundance-sensitive clearance of SOCE-mediated Ca2+ transients, whereas PMCA4a reduced cytosolic Ca2+, resulting in the establishment of a higher than baseline cytosolic Ca2+ concentration. Mathematical modeling showed that slow activation was critical to the sustained oscillation induced by the "slow" PMCA4b pump. The modeling and experimental results indicated that the distinct properties of PMCA isoforms differentially regulate the pattern of SOCE-mediated Ca2+ transients, which would thus affect the activation of downstream signaling pathways.