Environmentally persistent free radicals (EPFRs) are combustion products present in substantial numbers on atmospheric particulate matter that have half-lives of days to years. EPFRs can induce oxidative stress (OS) via Fenton reactions (H2O2+ Fe2+→• OH+ OH−+ Fe3+) in biological systems and are associated with pulmonary pathology. The mechanistic links between EPFR exposure and respiratory diseases are unclear. The aim of this study was to profile genes involved in the response of human airway epithelial cells to EPFRs. Primary human nasal epithelial cells were collected from healthy adults and were grown and differentiated at air-liquid interface. The well-differentiated epithelia were exposed to 1mg/cm2 EPFRs for four hours or 50mM H2O2 (oxidant control) for an hour, and responses measured using RT² Profiler PCR Array Oxidative Stress Gene Expression at 24-hour post-exposure. The function, upstream regulators, canonical pathways were analyzed by QIAGEN Ingenuity Pathway Analysis software. Gene-gene interaction was determined using GeneMANIA data base. 8 genes were upregulated with both EPFR and H2O2 exposure, 9 genes were exclusively upregulated following EPFR exposure, and 4 genes were exclusively upregulated with H2O2 exposure. 9 genes were down-regulated with both EPFR and H2O2 exposure, 6 genes were exclusively down-regulated after EPFR exposure, and 4 genes were exclusively down-regulated with H2O2 exposure. AOX1, HMOX1, SPINK1 were substantially upregulated with EPFR (7.4-fold, 5.3-fold, 40-fold, respectively) and H2O2 (5-fold, 3.2-fold, 24.7-fold, respectively) exposure. These are antioxidant genes associated with NRF2. SEPP1 was significantly down-regulated following EPFR (-7.4-fold) and H2O2 (-5.3-fold) exposure. A reduction in SEPP1 can induce reactive oxygen species production. The network diagram of EPFR exposure upregulated gene is shown in Figure1. Both EPFRs and H2O2 significantly upregulated NRF2-mediated OS response genes. EPFRs negatively affected the ferroptosis signaling pathway, a type of programmed cell death, which indicates that the well-differentiated respiratory epithelium was able to response and act redox reaction when exposure to sublethal concentration of EPFRs. Our results demonstrate that NRF2 plays an important role in response to EPFR and H2O2 exposure, and EPFRs can induce multiple genes related to antioxidant response, metal ion homeostasis, and fatty acid metabolism.