We investigated EGFR and HER-2 status in brain metastatic non-small cell lung cancer (NSCLC) and compared them to EGFR and HER-2 status of primary NSCLC. Evaluated were 66 cases of brain metastatic NSCLC, including 20 cases of corresponding primary NSCLC. HER-2 status was investigated by immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH), and EGFR status was evaluated by IHC. HER-2 overexpression and/or amplification was/were observed in three cases (4.5 %) of 66 cases of brain metastatic NSCLC, and 23 cases (34.8%) demonstrated EGFR overexpression. Among 20 cases of primary and corresponding metastatic NSCLC, one case showed HER-2 overexpression and amplification in both primary and metastatic tumor. On the other hand, EGFR overexpression was noted in four cases of primary NSCLC and nine cases of metastatic NSCLC. Five cases showed EGFR gain in metastatic NSCLC. Brain metastatic NSCLC demonstrated different expression patterns of the abovementioned biomarkers, particularly EGFR when compared to primary NSCLC. Therefore, HER-2 and EGFR status are suggested to be evaluated in brain metastatic NSCLC for targeted monotherapy.