Fundamental understanding of thermodynamic of phase separation plays a key role in tuning the desired features of biomedical devices. In particular, phase separation of ternary solution is of remarkable interest in processes to obtain biodegradable and biocompatible architectures applied as artificial devices to repair, replace, or support damaged tissues or organs. In these perspectives, thermally induced phase separation (TIPS) is the most widely used technique to obtained porous morphologies and, in addition, among different ternary systems, polylactic acid (PLLA)/dioxane/water has given promising results and has been largely studied. However, to increase the control of TIPS-based processes and architectures, an investigation of the basic energetic phenomena occurring during phase separation is still required. Here we propose an experimental investigation of the selected ternary system by using isothermal titration calorimetric approach at different solvent/antisolvent ratio and a thermodynamic explanation related to the polymer-solvents interactions in terms of energetic contribution to the phase separation process. Furthermore, relevant information about the phase diagrams and interaction parameters of the studied systems are furnished in terms of liquid-liquid miscibility gap. Indeed, polymer-solvents interactions are responsible for the mechanism of the phase separation process and, therefore, of the final features of the morphologies; the knowledge of such data is fundamental to control processes for the production of membranes, scaffolds and several nanostructures. The behavior of the polymer at different solvent/nonsolvent ratios is discussed in terms of solvation mechanism and a preliminary contribution to the understanding of the role of the hydrogen bonding in the interface phenomena is also reported. It is the first time that thermodynamic data of a ternary system are collected by mean of nano-isothermal titration calorimetry (nano-ITC). Supporting Information is available.