Epidermal growth factor receptor (EGFR) mutation analysis is necessary and important in clinical practice. But sometimes advanced lung cancer is diagnosed by cytology or inadequate specimens for DNA extractions. This study was aimed to inves-tigate the association of EGFR mutations with clinicopathologic features in small biopsy specimens. The medical records of 359 lung adenocarcinoma patients were reviewed. All the specimens of these patients were investigated for EGFR mutations (Exon 18-21) by direct sequencing method. EGFR mutations were present in 37.6%, and the majority of them was exon 19 deletions (60.7%). The incidence of EGFR mutations was the highest in never-smoked women patients (54.6%). According to the histologic subtype, EGFR mutations were more frequently observed with acinar and lepidic components, conversely infrequently with solid and mucinous components. The protein expression of TTF-1 was also related with the frequency of EGFR mutations (45.7%). We can ascertain that incidence of EGFR mutations is associated with gender and smoking history in small biopsy specimens. Acinar and lepidic subtype of histology, even if the histology comfirmed by only small biopsies, can predict the high frequency of EGFR mutations. When the specimens are not enough for DNA extractions and re-biopsy is incapable, the clinicopathologic features can predict the EGFR mutation status carefully but it cannot replace the mutation analysis.