The purpose of this study was to demonstrate the beneficial effect of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in the treatment of leptomeningeal metastasis (LM) for a select group of non-small cell lung cancer (NSCLC) patients who had a sensitive EGFR mutation or good predictive clinical factors for EGFR TKI treatment. Eleven patients with NSCLC and LM were treated with a standard dose of erlotinib (n=9), or higher than standard dose of gefitinib followed by erlotinib (n=2). They were treated with various therapies including whole brain radiotherapy or intrathecal chemotherapy for CNS lesion previously and concurrently with EGFR TKI. Nine of 11 patients showed overt improvement in ECOG performance status. Six patients were alive >6 months, and 2 additional patients were alive 2.5+ and 4.4+ months with clinical improvement. Two patients showed responses to higher than standard dose of gefitinib. The median overall survival was not reached. In conclusion, EGFR TKIs are effective in the treatment of LM from NSCLC when patients were selected properly.