Current choices of second-line chemotherapy regimens for patients with advanced non-small-cell lung cancer (NSCLC) are extremely limited. We applied a new strategy of using nab-paclitaxel as single chemotherapy regimen in second-line setting for patients with unsuccessful first-line chemotherapy. The efficacy and safety were compared with patients who received standard second-line regimen pemetrexed. Patients with stage IIIB/IV NSCLC and unsuccessful first-line platinum-based chemotherapy were randomly divided into two arms. Arm I received pemetrexed 500 mg/m(2) intravenously (i.v.) on day 1 of 3-week cycle. Arm II received nab-paclitaxel 150 mg/m(2) i.v. on days 1 and 8 of 3-week cycle. The primary endpoint was overall survival (OS). One hundred and eleven patients were randomly assigned to receive pemetrexed (n = 56) and nab-paclitaxel (n = 55). Median OSs were 9.4 months (95% CI 7.1-12.5 months) for pemetrexed and 9.9 months (95% CI 8.2-11.9 months) for nab-paclitaxel. Median PFS was 4.6 months (95% CI 2.7-6.1 months) for pemetrexed and 5.1 months (95% CI 3.9-7.4 months) for nab-paclitaxel. While no CR was reported for either treatment, PRs + SDs were seen in 32/56 (57.1%) patients in pemetrexed arm and 36/55 (65.5%) patients in nab-paclitaxel arm. Grade 3 and grade 4 adverse events were comparable between two treatment arms. New second-line chemotherapy single-regimen nab-paclitaxel showed equivalent efficacy and toxicity profiles as pemetrexed in treating patients with NSCLC.