The oleate capped NaYF 4 : Yb / Er upconversion nanoparticles (OA-UCNPs) were firstly synthesized by the thermal decomposition method and subsequently converted to water-dispersible, ligand-free UCNPs (LF-UCNPs) via an easy acid treatment process. The interaction of LF-UCNPs with bovine serum albumin (BSA) was then investigated. The binding of LF-UCNPs with BSA was confirmed by the static quenching of intrinsic fluorescence of BSA upon addition of LF-UCNPs. The spectra of synchronous fluorescence and circular dichroism (CD) of BSA in the absence and presence of LF-UCNPs revealed that the presence of LF-UCNPs led to a slight conformational change of BSA, suggesting a minor nanotoxicity of LF-UCNPs toward BSA.