Phase-change random access memory (PCRAM) holds great promise as a future non-volatile memory technology. All PCRAM devices have an inextricable relationship with thermodynamics. To make a memory cell crystallize or amorphize by injecting and removing thermal energy as a repetitive memory cycle results in the generation of entropy. In the study and development of PCRAM, the entropic part in the total energy has been neglected in the thermo-dynamical system. In this paper, we discuss entropic energy losses through simple calculations based on the Sackur–Tetrode equation and compare the results with those obtained by first-principles computer simulations. In addition, using a structure specific entropy generation model, we verify how much input energy is wasted in phase-change memory cells fabricated with a Ge2Sb2Te5 alloy-layer or a simulation optimized [(GeTe)2(Sb2Te3)4]7 multilayer structure. According to a detailed analysis, the entropy derived from application of the Sackur–Tetrode equation is in good agreement with results derived from first-principles simulations. Our experimental device fabricated using an entropy-controlled phase-change design resulted in significant efficiency improvements. Relative to a Ge2Sb2Te5 alloy-layer device, the new multilayer device exhibited a 82% improvement in energy efficiency for a transition from the high- to the low-resistivity state and with a 64% improvement in efficiency for a transition from the low- to the high-resistivity state. This new entropic-energy-loss optimized device was able to return to the high-resistivity state at approximately the same current as that required for the low-resistivity state of the alloy device.