Signaling pathways activated by epidermal growth factor receptors (EGFRs) are important in lung carcinogenesis. New treatment strategies with EGFR-targeting drugs provided improvements in management of lung cancer. However, molecular mechanisms underlying resistance to these drugs need to be evaluated. Surgically resected samples were obtained from 50 patients with non-small-cell-lung cancer. PTEN, Mcl-1 and EGFR protein expression levels were evaluated by Western-blot. Direct sequencing was performed to investigate EGFR tyrosine kinase domain mutations. We detected c.2235-2249 (pGlu746-Ala750del) mutation in exon 19 in two patients with adenocarcinoma histology. Elevated expression levels of both Mcl-1 isoforms (Mcl-1S and Mcl-1XL) and EGFR proteins were found in 15 (30%) and 23 (46%) of the cases, respectively. Reduced PTEN protein expression levels were observed in 17 (34%) of the cases. PTEN expression level was reduced in 26% of cases that showed increased EGFR expression. Also, increased expression of Mcl-1 protein was observed in 26% of cases with EGFR overexpression. One of the cases harboring pGlu746-Ala750del mutation had increased levels of Mcl-1 and decreased PTEN expression levels. Our results indicate that, in addition to lack of PTEN expression, elevated levels of the Mcl-1 protein might be one of the important intrinsic mechanisms protecting non-small-cell-lung cancer cells from apoptosis induced by several compounds. Therefore, EGFR mutations in conjunction with evaluation of Mcl-1 and PTEN expression levels in large cohorts might provide important clues for improvements of new treatment strategies in non-small-cell-lung cancer management.