Plasma membrane Ca2+ ATPases (PMCAs) are known targets of phosphatidylinositol-4,5-bisphosphate (PIP2), but if and how they control the PIP2 pool has not been considered. We demonstrate here that PMCAs protect PIP2 in the plasma membrane. Comparison of active and inactive PMCAs indicates that the protection operates by 2 mechanisms; one requiring active PMCA, the other not. It appears that the mechanism requiring activity is the removal of the Ca2+ required for sustained phospholipase C (PLC) activity, while the mechanism not requiring activity is PIP2 binding. We show that in PMCA overexpressing cells, PIP2 binding can lead to less IP3 and diminished Ca2+ release from intracellular Ca2+ pools. Inspection of a homology model of PMCA suggests that PMCAs have a conserved cluster of basic residues forming a “blue collar” at the interface between the membrane core and the cytoplasmic domains. By molecular dynamics simulation we found that the blue collar forms four binding pockets for the phosphorylated inositol head group of PIP2; these pockets bound PIP2 strongly and frequently. Our studies suggest that by having the ability to bind PIP2, PMCAs can control the accessibility of PIP2 for PLC and other PIP2 mediated processes.