Although a secondary mutation and the epithelial-to-mesenchymal transition (EMT) are encountered very often in patients received the EGFR-TKI targeted treatment. The entire detrimental morphological change of the cancer entity was rare reported. Herein we report a case that acquired resistance to EGFR-TKI with T790M mutation and complete EMT morphological change of the tumor tissue. The primary lung tumor from a 52-year-old woman was diagnosed with moderate differentiated adenocarcinoma, with intensively positiveTTF-1 and E-cadherin in differentiated glandular structure but not the budding cancer cell cluster which with an intensive Vimentin staining. Molecular analysis revealed an EGFR exon 19 deletion and with an excellent response to Gefitinib treatment. Microscopic examination of recurred tumor specimens revealed a diffuse poorer differentiated proliferation of atypical cells. Immunostaining showed intensive Vimentin but almost completely negative for E-cadherin and TTF-1. Genetic analyses revealed T790M mutation. It is worth noting that rare clinical studies have been reported that acquired EGFR-TKI resistant lung adenocarcinoma underwent T790M mutation and almost complete EMT together. More significantly, the similarity of poorly differentiated cancer cell cluster in the primary lesions to recurred tumor lesions, which may pre-harbor drug resistance mutation should not be neglected underneath the predominant morphologic patterns.