Background Lung cancer with mutations in the epidermal growth factor receptor (EGFR) is one of the leading causes of cancer-related death, and non-small-cell lung cancer (NSCLC) has captured the attention of researchers. These mutations occur within EGFR exons 19, 18, 20, and 21.Objective Our study aimed at determining the prevalence of the mutation in the biopsy samples of NSCLC patients in Egypt.Patients and methods In this study, 195 adenocarcinoma (ACA) patients with NSCLC were diagnosed and graded on the basis of histopathology using hematoxylin and eosin stain. The samples were subjected to immunohistochemistry studies and were confirmed as positive using TTF1 and as negative using P63. The positive samples were subjected to PCR amplification for EGFR mutation study.Results On the basis of hematoxylin and eosin-stained sections, 15 of 195 ACA patients were of grade I, 160 patients (the majority) were of grade II, and 20 patients were of grade III (195 vs. 20, P < 0.001; 60 vs. 15, P < 0.001; 15 vs. 20, P < 0.37, statistically nonsignificant). Of the 195 ACA patients, 68 (34.8%) had tumor-associated EGFR mutations, 40 (58.8%) patients had deletion in codon 19, 16 (23.6%) patients had deletion of L858R in codon 21, six (8.8%) patients had insertion in codon 20, three (4.4%) patients had insertion in codon 18, and three (4.4%) patients had multiple mutations [40 vs.16, P < 0.001; 40 vs. 6, P < 0.001 (highly significant); 40 vs. 3, P < 0.001]. As regards sex, the incidence of EGFR mutations was higher in women (41, 60.3%) than in men (27, 39.7%) (68 vs. 41, P < 0.05; 68 vs. 27, P < 0.05; 41 vs. 27, P < 0.05). Tumors with an activating EGFR mutations were more likely to be from nonsmokers (43/63.3%) than from smokers (25/36.7%) (43 vs. 25, P < 0.001, significant). ConclusionThe current study has revealed that 34.8% of patients with NSCLC have tumor-associated EGFR mutations. Of which, 58.8% of the mutations were exon 19 deletions. EGFR mutations were more often found in tumors from female nonsmokers with ACA histopathology.