Background: Erlotinib and gefitinib have been shown to have similar activity for EGFR mutation-positive (EGFRm+) NSCLC. Since the steady-state plasma trough concentration of erlotinib is approximately 3.5 times higher than that of gefitinib when administered at the respective approved dose, treatment with low-dose erlotinib may be as effective as full-dose therapy, with less toxicity and cost. Methods: Eligible patients had advanced EGFRm+ NSCLC with 1 to 3 prior chemotherapy treatments. Erlotinib with the initial daily dosage of 50 mg was administered. Dose was escalated to 150 mg in case of not achieving CR or PR by RECIST criteria at the evaluation after the first 4 weeks of treatment. Erlotinib was continued until disease progression or unacceptable toxicities. The primary endpoint was independent committee-determined objective response rate (ORR) to the low-dose erlotinib, with target ORR of 70% and threshold of 50%. The sample size was calculated to be 40, and the primary endpoint was met if 26 or more patients responded. Results: Thirty-four patients were enrolled between Apr. 2010 and Nov. 2012. Males/females 20/14; median age 67 (range 38-81); PS 0/1 16/18; Ad/Sq 33/1. One patient was excluded from evaluation due to absence of active tumor. The study was closed early according to the protocol definition when 15 of 33 evaluable patients failed to achieve CR/PR, making it impossible to meet the primary endpoint. ORR was 54.5% (95% C.I.: 36.4% to 71.9%), with disease control rate of 84.8%. Median progression free survival and overall survival were 9.5 months and 28.5 months, respectively. Grade 3 toxicities were 2 cases with transient neutropenia, and 1 with reversible AST/ALT elevation. No grade 4 toxicity or treatment-related death was observed. Conclusions: This trial is the first prospective study evaluating low-dose erlotinib. Although it appeared to have a certain efficacy, the primary endpoint was not met. Because of its low toxicity, it may be worth further evaluation in elderly and/or frail patients. Trial registry UMIN #000003313.