The surface chemistry of biomaterials can have a significant impact on their performance in biological applications. Our recent work suggests that cerium oxide nanoparticles are potent antioxidants in cell culture models and we have evaluated several therapeutic applications of these nanoparticles in different biological systems. Knowledge of protein adsorption and cellular uptake will be very useful in improving the beneficial effects of cerium oxide nanoparticles in biology. In the present study, we determined the effect of zeta potential of cerium oxide nanoparticles on adsorption of bovine serum albumin (BSA) and cellular uptake in adenocarcinoma lung cells (A549). The zeta potential of the nanoparticles was varied by dispersing them in various acidic and basic pH solutions. UV-visible spectroscopy and inductively coupled plasma mass spectrometry (ICP-MS) were used for the protein adsorption and cellular uptake studies, respectively. Nanoceria samples having positive zeta potential were found to adsorb more BSA while the samples with negative zeta potential showed little or no protein adsorption. The cellular uptake studies showed preferential uptake for the negatively charged nanoparticles. These results demonstrate that electrostatic interactions can play an important factor in protein adsorption and cellular uptake of nanoparticles.