Epirubicin was effective for the treatment of non-small cell lung carcinoma (NSCLC). This study compared the efficacy and safety of gemcitabine plus conventional-dose epirubicin (GE) with gemcitabine–cisplatin (GC) as first-line chemotherapy for stage IIIB/IV NSCLC and evaluated the predictive value of nuclear expression of excision repair cross-complementing group 1 (ERCC1) and topoisomerase IIα (TopoIIα) on treatment outcome.Patients were randomized to GE (gemcitabine, 1000mg/m 2 on days 1, 8, and 15 and epirubicin, 70mg/m 2 on day 15) or GC (gemcitabine, 1000mg/m 2 on days 1, 8, and 15 and cisplatin, 80mg/m 2 on day 15). Treatment cycles were repeated every 4 weeks. Immunohistochemical study of ERCC1 and TopoIIα was done for patients with available tumor specimens.The response rate was 31.0% (95% CI 16.4–45.5%) for GC (n=41) and 37.2.0% (95% CI 22.2–52.3%) for GE (n=39). No significant differences in median time-to-treatment-failure (TTF) (GC, 6.1 months; GE, 6.2 months) or overall survival (GC, 13.2 months; GE, 21.5 months) were found between the two arms. Grade 3/4 neutropenia and febrile neutropenia were more common in GE. However, delay of protocol treatment due to leukopenia was similar between the two arms. Patients with expression of both ERCC1 and TopoIIα had a significantly shorter TTF (median 2.4 months, 95% CI 0.7–4.1 months) than other patients (median 8.8 months, 95% CI 5.8–11.8 months) (p=0.04).GE regimen is effective and well-tolerated for NSCLC patients. Expression of both ERCC1 and TopoIIα may be associated with poor response to chemotherapy.