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Future biomedical applications of nanoparticles will encounter these particles with patients' serum which might affect the properties and stability of quantum dots and serum proteins at the desired site of action. Therefore, it is essential to clarify the patient-specific serum components, serve as major interaction partners, the spatial distribution of these, and consequently the time-dependent effects of nanoparticle–protein interaction. Here, a biochemical and structural study was performed on the protein corona formation and the corresponding interaction of different sizes of CdTe QDs with human serum proteins to determine if the mutual effects on optical properties by using electrophoresis, chemiluminescence, and fluorescence spectroscopy. The results revealed that interaction with human serum significantly enhanced the stability and photoluminescence of quantum dots. Structural studies of HSA-coated CdTe QDs also showed that corona formation has no adverse effects on protein structure, and the reduction in fluorescence emissions of HSA is due to the direct quenching of aromatics residues by the quantum dot. Improving nanoparticle properties, as well as the lack of structural changes in HSA, can be very useful in biomedical applications and in vivo studies where stability is important. Image 1 • The structural changes and optical properties of protein and CdTe QDs upon corona formation were investigated. • Interaction of quantum dots with human serum albumin significantly enhanced the stability and photoluminescence of QDs. • Structural studies of HSA-coated CdTe QDs showed that corona formation has no adverse effects on protein structure. • This study will help to predict the nanoparticle–cell interaction and to rate the biocompatibility of nanoparticles. [ABSTRACT FROM AUTHOR]