Purpose Platinum-based doublet chemotherapy has a major role in the treatment of patients with advanced non-small cell lung cancer (NSCLC). The weekly fractionated administration of cisplatin for patients with NSCLC has been shown to be active. Irinotecan and carboplatin are effective against NSCLC and demonstrated synergism with non-cross-resistance in preclinical studies. We conducted a phase II study of weekly combination of carboplatin and irinotecan as first-line chemotherapy for patients with advanced NSCLC. Methods From March 2009 to November 2011, 24 patients who were diagnosed with inoperable or metastatic NSCLC were enrolled. Treatment consisted of carboplatin at an AUC 2.5 mg/mL/min over 30-min intravenous infusion and irinotecan 65 mg/m 2 over 90-min intravenous infusion on day 1 and day 8, respectively. The treatment was repeated every 3 weeks. Results One patient (4.2 %) achieved complete response, and seven (29.2 %) showed partial response. Overall response rate was 33.3 %, with median response duration of 4.55 months. Nine patients had stable disease, and disease control rate was 70.8 %. With median follow-up of 12.8 months, median progression-free survival was 4.5 months (95 % CI 1.8–7.2), and median overall survival was 15.5 months (95 % CI 6.9–24.1). Major toxicity was myelosuppression. Grade 3–4 neutropenia and thrombocytopenia occurred in 50 and 20.8 % of patients, respectively. Two patients experienced febrile neutropenia. Non-hematologic toxicities were generally mild. One patient suffered grade 4 diarrhea, and one treatment-related death due to pneumonia was occurred. Conclusion The weekly combination of carboplatin and irinotecan showed favorable activity and manageable toxicity profiles in chemo-naïve patients with advanced NSCLC. Our results suggest that this regimen can be a reasonable chemotherapeutic option for patients with advanced NSCLC.