Background: The efficacy of erlotinib is controversial in patients with unknown EGFR mutational status. The aim of this study was to identify the clinicopathological factors that are predictive of erlotinob treatment outcomes for NSCLC patients with unknown EGFR mutational status. Materials and Methods: A retrospective analysis of 109 patients with advanced NSCLC who had previously failed at least one line of chemotherapy and received subsequent treatment with erlotinib (150 mg/day orally) was performed. A Cox proportional hazard model for univariate and multivariate analyses was used to identify the baseline clinical parameters correlating with treatment outcome, expressed in terms of hazard ratios (HRs) and 95% confidence intervals. Results: The median treatment duration was 15 weeks (range, 4-184). The disease control rate was 55%, including disease stability for >= 3 months for 40% of the patients. Median progression-free survival and median overall survival (OS) were 4.2 and 8.5 months, respectively. The Cox model indicated that an Eastern Cooperative Oncology Group performance status (ECOG PS) >= 2 (HR 3.82; p<0.001), presence of intra-abdominal metastasis (HR 3.42; p=0.002), 2 or more prior chemotherapy regimens (HR 2.29; p=0.021), and weight loss >5% (HR 2.05; p=0.034) were independent adverse prognostic factors for OS in NSCLC patients treated with erlotinib. Conclusions: This study suggests that NSCLC patients should be enrolled in erlotinib treatment after a first round of unsuccessful chemotherapy to improve treatment success, during which they should be monitored for intra-abdominal metastasis and weight loss.