Quantum dots are highly fluorescent and photostable, making them excellent tools for imaging. When using these quantum dots in cells and animals, however, intracellular biothiols (such as glutathione and cysteine) can degrade the quantum dot monolayer, compromising function. Here, we describe a label-free method to quantify the intracellular stability of monolayers on quantum dot surfaces that couples laser desorption/ionization mass spectrometry with inductively coupled plasma mass spectrometry. Using this new approach we have demonstrated that quantum dot monolayer stability is correlated with both quantum dot particle size and monolayer structure, with appropriate choice of both particle size and ligand structure required for intracellular stability.