Abstract BACKGROUND: Efficacy of second-line chemotherapy in platinum-pretreated non–small cell lung cancer (NSCLC) is poor. This study investigated efficacy of computed tomography–guided percutaneous fine-needle 5% ethanol-cisplatin intratumoral injection (CT-PFNECII) combined with second-line chemotherapy in patients with platinum-pretreated stage IV NSCLC. PATIENTS: Between October 2011 and July 2013, 34 eligible patients were randomly assigned to receive either CT-PFNECII combined with second-line chemotherapy (combination group, n = 17) or second-line chemotherapy alone (chemotherapy group, n = 17). The primary end points were the proportions of patients who achieved an overall response rate (ORR) and disease control rate (DCR). Secondary end points were median survival and progression-free survival (PFS). RESULTS: The ORR and DCR in the combination group were significantly higher than in the chemotherapy group (23.53% vs 11.76% for ORR, P < .01; and 58.82% vs 35.29% for DCR, P < .01). Compared with patients in the chemotherapy group, patients in the combination group had significantly longer PFS (5.4 months vs 3.0 months, P < .01) and median survival (9.5 months vs 5.3 months, P < .01). CONCLUSIONS: CT-PFNECII combined with second-line chemotherapy provided a higher response rate and improved survival than second-line chemotherapy for patients with platinum-pretreated stage IV NSCLC.