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Background Gefitinib is a first-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) that has become first-line treatment for patients with mutant EGFR non-small cell lung cancer (NSCLC). Despite its anti-tumor activity, the benefit of gefitinib in patients with wild-type EGFR NSCLC is debated. This work aimed to evaluate the effects of gefitinib on cisplatin-resistant wild-type EGFR NSCLC cells in in vitro and in vivo animal xenografts. Methods We established a cisplatin-resistant wild-type EGFR NSCLC cell line, H358R, to evaluate the cells’ sensitivity to gefitinib compared with that of parental cell line H358. We first tested the p-EGFR of gefitinib’s target in H358R and H358 cell line by western blot and immunofluorescence. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), clone formation assay, flow cytometry and annexin V-fluorescein/propidium iodide staining were used to investigate cellular proliferation and apoptosis of H358R/H358 cells treated with gefitinib, and the anti-tumor effect was evaluated in female BALB/c nude mice models of xenografts in vivo. Results EGFR and the downstream node molecules ERK and AKT were significantly more phosphorylated in H358R than in the parental cells and were inhibited by gefitinib. In H358R cells, gefitinib increased the inhibition of cell survival/proliferation, and the promotion of apoptosis in vitro. The increased anti-tumor effect was present also in H358R xenografts in vivo. Conclusions Abnormal activation of EGFR in H358R cells results in enhanced sensitivity to gefitinib. The improved efficacy of gefitinib on cisplatin-resistant wild-type EGFR NSCLC cells suggests that gefitinib as sequential therapy for patients with cisplatin-resistant wild-type EGFR NSCLC should be considered.