In a proof-of-concept study, we assessed different analytical and spectroscopic parameters for stability screening of differently sized beta-NaYF4:20 mol % Yb3+, % Tm3+ upconverion nanoparticles (UCNPs) exemplarily in the bioanalytically relevant buffer-phosphate buffered saline (PBS; pH 7.4) at 37 and 50 degrees C. This included the potentiometric determination of the amount of released fluoride ions, surface analysis with X-ray photoelectron spectroscopy (XPS), and steady-state and time-resolved fluorescence measurements. Based on these results, the luminescence lifetime of the 800 nm upconversion emission was identified as an optimum parameter for stability screening of UCNPs,and changes in particle surface chemistry.