<b><i>Objective:</i></b> Lung cancer represents the leading cause of cancer death. <i>EGFR</i> mutations, detected<b> </b>in 10-40% of lung adenocarcinomas, are an essential key to therapeutic management. <i>EGFR</i>-activated mutations comprise mainly deletions in exon 19 and point mutations in exon 21. Although histology is the traditional method of detection,<b> </b>we investigated the role of cytology in <i>EGFR</i> mutations. <b><i>Study Design:</i></b> A total of 774 lung cancers were studied for <i>EGFR</i> mutations (676 histological and 98 cytological samples), including 424 adenocarcinomas, 326 non-small cell lung carcinomas not otherwise specified, and 24 squamous cell carcinomas. <b><i>Results:</i></b> We had a total of 164 (21.2%) cases of mutations. Common mutations were short in-frame deletions in exon 19 (53.7%) and single-nucleotide substitutions in exon 21 (34.1%); less frequent mutations included single-nucleotide substitutions in exon 18 (3.7%) and in-frame insertions/deletions in exon 20 (8.5%). Histologically, <i>EGFR</i> mutations in exons 19 and 21 occurred in 19.4% and in exons 18 and 20 in 2.2%, while the rates cytologically were 13.3% for exons 19 and 21 and 5.1% for exons 18 and 20. <b><i>Conclusions:</i></b> The sensitivity for the detection of <i>EGFR</i> mutations in cytological samples overlaps histology, so the use of cytological material constitutes an adequate approach for treatment selection in patients with locally advanced or metastatic lung cancer.