Biodegradable nanoparticles made of Poly(lactide-co-glycolide) are increasingly proposed for the improvement of oral drug absorption, but also as carriers for the treatment of colonic diseases. Unfortunately, our knowledge of the digestibility of PLGA-NPs is rather limited. Therefore, we investigated the impact of pancreatin on the digestibility of PLGA-NPs stabilized with different emulsifiers. The pancreatin induced degradation was monitored by the pH-stat method and an enzymatic l-lactic acid assay. A high digestibility was found for poloxamer 188 and polysorbate 80 stabilized PLGA-NPs. The digestion could be blocked by Orlistat, indicating a major role of pancreatic lipase. PLGA-NPs stabilized with Poly(vinyl alcohol) (=PVA) were not digested at comparable surfactant concentrations (0.6%). However, PLGA-NPs stabilized with very low amounts of PVA (0.1%) were digestible. In conclusion, PLGA-NPs are substrates for the pancreatic lipase. The digestibility can be enhanced or blocked by the proper selection of the surfactant composition and concentration.