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Whether EGFRmutation occurs in lung squamous cell carcinoma (SCC) remains a controversial issue. Although numerous trials have shown positive response to tyrosine kinase inhibitors in SCC, these observations have not been well correlated with presence or absence of EGFRmutation. A complicating issue is that adenosquamous carcinoma, a mimic of SCC, frequently harbours EGFRmutations. We evaluated the EGFRmutation status of 191 cases initially diagnosed as SCC of lung origin in years 2000–2011, and performed a panel of markers including p40, p63, CK5/6, TTF-1, mucicarmine on the tissue microarray or tissue blocks from each case, to ascertain the squamous differentiation of each case. Four cases were found to have EGFRmutations, with three showing typical squamous morphological features and immunohistochemical profile on all available tumour blocks, and one reclassified as adenosquamous carcinoma. Mixed responses were noted for two of the patients with EGFR-mutated SCC treated with tyrosine kinase inhibitors. In conclusion, we report that a small subset of rigorously proven SCC harbours EGFRmutation. It also appears in our cohort that EGFR-mutated tumours, in the context of SCC, may have relatively poor response to tyrosine kinase inhibitors.