Due to unique surface chemistries and the ability to easily functionalize their surface, amorphous silica nanoparticles are being assimilated into medicinal and consumer products at an increasing rate. Subsequently, there is an emergent need to understand the interactions of these particulates with biological systems in an attempt to mitigate toxicity. The identification of susceptible or resistant cell types of the pulmonary system remains a critical step in the development of toxicity assessments for nanoparticle-based platforms. Specific to this study, the cellular responses of A549 lung epithelial and MeT-5A pleural mesothelial cell lines as a means of detecting nanoparticle-induced oxidative stress were examined. Basal expression and cellular antioxidant activity, including SOD, CAT, and GSH, were examined prior to H2O2 and ?30 nm SiO2 (0.01–100 mg/L) exposures. Dose–response observations were made regarding oxidant production, cytotoxicity, GSH depletion and NRF2 transcription factor activation. Results indicated that, while both cell types exhibited susceptibility to H2O2 and SiO2-induced oxidative stress and damage, the A549 cell line was relatively more resilient.