Objective: To investigate whether combination chemotherapy with cisplatin, etoposide, and irinotecan was better than topotecan alone as second-line chemotherapy in patients with sensitive relapsed small cell lung cancer (SCLC). Method: Between September, 2014 and September, 2017, the patients'data were collected in Jilin Province Cancer Hospital. All patients were diagnosed with sensitive relapsed SCLC. Thirty-six patients received combination chemotherapy containing cisplatin plus etoposide plus irinotecan, and 42 patients received topotecan alone. Combination chemotherapy consisted of five 2-week courses of intravenous cisplatin 25 mg/m2 on days 1 and 8, intravenous etoposide 60 mg/m2 on days 1-3, and intravenous irinotecan 90 mg/m2 on day 8. Topotecan therapy consisted of at least one course of intravenous topotecan 1.5 mg/m2 on days 1-5, every 3 weeks. The primary endpoints were progression-free survival (PFS) and overall survival (OS), and safety was assessed in all patients who received at least one dose of drugs. Results: PFS was significantly longer in the combination chemotherapy group [median 5.3 months, 95% confidence interval (CI) 4.3-5.8] than in the topotecan group (3.2 months, 95% CI: 2.7-4.0;P=0.0030); OS was also significantly increased in the combination chemotherapy group (median 16.3 months, 95% CI: 13.8-19.1) than in the topotecan group (13.1 months, 95% CI: 10.2-15.4; P=0.0097). The most common grade 3/4 adverse events were neutropenia [31 (86.1%) patients in the combination chemotherapy group vs. 28 (66.7%) patients in the topotecan group], anemia [26 (72.2%) vs. 10 (23.8%)], leucopenia [29 (80.6%) vs . 21 (50.0%)], and thrombocytopenia [13 (36.1%) vs . 11 (26.2%)]. One treatment-related death (febrile neutropenia with pulmonary infection) occurred in the combination chemotherapy group, and none occurred in the topotecan group. Conclusions:Combination chemotherapy with cisplatin plus etoposide plus irinotecan could be considered a treatment option in second-line che-motherapy for selected patients with sensitive relapsed SCLC. However, the combination chemotherapy group had a higher incidence of adverse events than the topotecan group, and appropriate drug dosages should be explored.