<b><i>Objectives:</i></b> We aimed to evaluate the prevalence and predictive role of <i>c-MET</i> expression and <i>EGFR</i> mutation in the efficacy of erlotinib in non-small-cell lung cancer (NSCLC). <b><i>Methods:</i></b> We prospectively recruited 196 patients with stage IV or recurrent NSCLC treated with erlotinib after failure of first-line chemotherapy. Immunohistochemistry was used to evaluate <i>c-MET</i> overexpression, silver in situ hybridization (SISH) to assess gene copy number, and real-time polymerase chain reaction to detect <i>EGFR</i> mutations, respectively, in tumor tissue. <b><i>Results:</i></b> The major histologic type was adenocarcinoma (66.8%). <i>c-MET</i> was overexpressed in 55.8% (87/156) and dominant in females as well as non-squamous histology. Although <i>c-MET</i> gene amplification and high polysomy were observed in 2.0% (3/152) and 11.2% (17/152), they did not correlate with any characteristics. <i>EGFR</i> mutation was detected in 13.1% (20/153). The objective response rate of erlotinib was higher (61.1 vs. 3.7%, <i>p</i> &#x3c; 0.001) and the median progression-free survival (PFS) was longer (10.2 vs. 1.9 months, <i>p</i> &#x3c; 0.001) in EGFR-sensitizing mutations. However, <i>c-MET</i> positivity did not show a significant correlation with response to erlotinib or PFS. <b><i>Conclusion:</i></b> We reconfirmed <i>EGFR</i> mutation as a strong predictive marker of NSCLC. However, <i>c-MET</i> positivity was not associated with response or PFS, although <i>c-MET</i> overexpression correlated with some clinical characteristics.