This phase II study was conducted to investigate the efficacy and safety of irinotecan (CPT-11) and ifosfamide as second-line chemotherapy for relapsed small cell lung cancer (SCLC). Eligibility criteria included histologically or cytologically confirmed SCLC, prior chemotherapy including platinum + etoposide, and measurable or evaluable disease. CPT-11 (80 mg/m2) was administered intravenously on days 1, 8 and 15, while ifosfamide (1.5 g/m2) was given on days 1 through 3 every 4 weeks. Thirty-four patients (29 men) with a median age of 69 years (range 42–77) and a median Eastern Cooperative Oncology Group (ECOG) performance status of 1 (range 0–2) were enrolled. The response rate was 52.9% (95% confidence interval: 29.8–64.9%) with 2 complete responses and 16 partial responses. Our analyses of prognostic factors showed risk factors assessed before receiving second-line chemotherapy, which were the number of metastatic sites, performance status and the type of relapse. WHO grade 3–4 neutropenia was recorded in 52.9% of the patients, grade 3 diarrhea in 5.9%. The combination of CPT-11 and ifosfamide demonstrated clinical efficacy in relapsed SCLC with a favorable toxicity profile, particularly for performance status 0–1 and sensitive cases with only one metastatic site.