The toxicity of engineered nanoparticles is expected to depend in part on their stability in biological systems. To assess the biodurability of engineered nanomaterials in the human digestive system, we adapted an in vitro assay previously used to evaluate the bioaccessibility of metals in contaminated soils. The compositions of the simulated gastric and intestinal fluids, temperature and residence times were designed to closely mimic conditions in the stomach and duodenum of the small intestine. We demonstrated the utility of the assay using CdSe_core/ZnS_shell quantum dots functionalized with polyethylene glycol (PEG) thiol of two different molecular masses (PEG₃₅₀ and PEG₅₀₀₀). Under gastric conditions, removal of the PEG ligand diminished the stability of PEG₃₅₀-quantum dot suspensions, while PEG₅₀₀₀-quantum dots were severely degraded. Inclusion of the glycoprotein mucin, but not the digestive protein pepsin, in simulated gastric fluids provided both PEG₃₅₀- and PEG₅₀₀₀-coated quantum dots partial protection from transformations induced by gastric conditions.