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Understanding the molecular driving forces that underlie membrane protein-lipid interactions requires the characterization of their binding thermodynamics. Here, we employ native mass spectrometry in conjunction with a variable temperature apparatus to determine the thermodynamics of individual lipid binding events to the human G-protein-gated inward rectifier potassium channel, Kir3.2. We find that Kir3.2 displays distinct thermodynamic strategies to engage phosphatidylinositol (PI) and phosphorylated forms thereof. The addition of a 4’- phosphate to PI with 18:1-18:1 (DO) tails results in an increase in favorable entropy along with an enthalpic penalty. The binding of PI with two or more phosphates is more complex where lipids bind to Kir3.2 with the cytoplasmic domain in either a docked or extended configuration. Remarkably, the interaction of 4,5-bisphosphate DOPI (DOPI(4,5)P2) with Kir3.2 is solely driven by a large, favorable change in entropy. Installment of a third 3’-phosphate to DOPI(4,5)P2 results in an alternative thermodynamic strategy for the first binding event whereas each successive binding event shows strong enthalpy-entropy compensation. PI(4,5)P2 with 18:0-20:4 tails results in an inversion of thermodynamic parameters where the change in enthalpy now dominates. Collectively, the data show that entropy can indeed play important roles in regulating membrane protein-lipid interactions.