The cytosolic Group IVA phospholipase A2 (GIVAPLA2) translocates to intracellular membranes to catalyze the release of lysophospholipids and arachidonic acid. GIVAPLA2 translocation and subsequent activity is regulated by its Ca2+-dependent phospholipid binding C2 domain. Phosphatidylinositol 4,5-bisphosphate (PI-4,5-P2) also binds with high affinity and specificity to GIVAPLA2, facilitating membrane binding and activity. Herein, we demonstrate that GIVAPLA2 possessed full activity in the absence of Ca2+ when PI-4,5-P2 or phosphatidylinositol 3,4,5-trisphosphate were present. A point mutant, D43N, that is unable to bind Ca2+ also had full activity in the presence of PI-4,5-P2. However, when GIVAPLA2 was expressed without its Ca2+-binding C2 domain (DeltaC2), there was no interfacial activity. GIVAPLA2 and DeltaC2 both had activity on monomeric lysophospholipids. DeltaC2, but not the C2 domain alone, binds to phosphoinositides (PIPns) in the same manner as the full-length GIVAPLA2, confirming the location of the PIPn binding site as the GIVAPLA2 catalytic domain. Moreover, proposed PIPn-binding residues in the catalytic domain (Lys488, Lys541, Lys543, and Lys544) were confirmed to be essential for PI-4,5-P2-dependent activity increases. Exploiting the effects of PI-4,5-P2, we have discovered that the C2 domain plays a critical role in the interfacial activity of GIVAPLA2 above and beyond its Ca2+-dependent phospholipid binding.