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Nuclear factor erythroid-related factor 2(NRF2) encodes a transcription factor that induces expression of cytoprotective proteins upon oxidative stress and oncogenicNRF2mutations have been found in lung and head/neck cancers that inactivate KEAP1-mediated degradation of NRF2. The aim of this study was to catalogueNRF2mutations in other human cancers. For this, we analysed 1145 cancer tissues from carcinomas from oesophagus, skin, uterine cervix, lung, larynx, breast, colon, stomach, liver, prostate, urinary bladder, ovary, uterine cervix, and kidney, and meningiomas, multiple myelomas, and acute leukaemias by single-strand conformation polymorphism (SSCP) assay. We detectedNRF2mutations in oesophagus (8/70; 11.4%), skin (1/17; 6.3%), lung (10/125; 8.0%), and larynx (3/23; 13.0%) cancers. Of note, all of the 22 mutations except one were found in squamous cell carcinomas (SCCs) (95.5%). The mutations were observed within or near DLG and ETGE motifs that are important in NRF2 and KEAP1 interaction. All of the oesophageal SCCs and skin SCCs with theNRF2mutations showed increased NRF2 expression in the nuclei. However, none of the SCCs from oesophagus and skin harbouredKEAP1mutation. Our study demonstrated here thatNRF2mutation occurs not only in lung and head/neck cancers, but also in oesophageal and skin cancers. Our data suggest that theNRF2mutation plays a role in the development of SCC and is a feature of SCC. Copyright © 2009 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.