In this study the effect of mesoporous SiO2 nanoparticles (MNPs) on the thermal stability of human serum albumin (HSA) in sodium buffer phosphate at pH 7.4 and in MilliQ water pH 6.3, as well as the thermodynamics of protein-MNPs interactions were evaluated against the protein corona (PC) formation in that media, depending on the nanoparticle surface area. The chemical and structural characterization of the studied materials (mesoporous SiO2 with particle size of 300 nm and 270 nm) was realized by IR, BET surface area, BJH pore size and volume analysis, scanning electron microscopy (SEM), DLS (dynamic light scattering) size distribution and zeta potential. The characterization of the protein corona formed by incubating the NPs with a biological fluid, in this case HSA, was realized by BCA assay for the quantification and SDS-PAGE for the qualification of the proteins that form the protein corona. The changes in the thermal behaviour of HSA (both free in solution and adsorbed to nanometer-sized oxide particles) were studied by using NanoDSC-TA Instruments equipment. SiO2 MNPs have a destabilizing effect on the thermal unfolding of HSA. Compared to the thermal denaturation of free protein in sodium buffer phosphate at pH 7.4, lower values of the transition temperature for adsorbed protein were observed, indicating that the stability of the protein when it forms the corona is less stable than the free albumin. Furthermore, enthalpy (ΔH), and heat capacity (Cp) values for the adsorbed protein on MNPs are bigger than the corresponding values in the MNP absence, due to the presence of water molecules when the protein corona is formed. Within the studied samples the one that has a higher protein corona (262 μg HSA/mg MNP), and at the same time more surface area (827.3 m2/g) and a higher pore (38.8 Å), has less increase comparing with the free albumin and the MNP that has the lower protein corona (81 μg HSA/mg MNP), less surface area (780.7 m2/g) and pore (36.0 Å). For the study of HSA-MNPs interaction, isothermal calorimetric measurements in water at 310 K were performed using an ITC200 microcalorimeter. Thermodynamic characteristics of protein-MNPs interactions (the binding stoichiometry n, the binding constant K, the changes of binding enthalpy ΔH and the binding entropy ΔS) were obtained. The binding of HSA on SiO2 MNPs’ surface is a complex proces. At the beginning of the titrations, the endothermic effect indicates the dominance of hydrophobic interactions. It is followed by an exothermic effect implying a predominant role of polar interactions, e.g. ionic and/or hydrogen bond formation. The less ΔH and the high K correspond to higher PC.