AbstractCell and vesicle adhesion is believed to be dictated by the balance between a local interaction potential, which represents the sum of all attractive and repulsive forces and the elastic energy. Changing the mechanical properties of the membrane therefore offers a sensitive tool to control vesicle adhesion. Here, we take advantage of the dramatic changes in area per molecule, fluidity and compressibility during lipid phase transition to alter vesicle adhesion. We demonstrate that driving a giant unilamellar vesicle (GUV) through its phase transition by increasing the temperature leads to a wetting transition of the vesicle onto a pure glass substrate. Analysing vesicle shape and the adhesion area shows that the vesicle is strongly adhered and that the wetting process follows exactly the melting transition of the lipid membrane. We provide evidence that the linear relationship between change in area and enthalpy during lipid phase transition can be applied to individual vesicles as its application correctly extracts the heat capacity profile of DPPC vesicles from our adhesion experiments. It clearly demonstrates that this wetting process is driven by the coupling of mechanical and thermodynamic properties in lipid membranes.