The efficacy of salvage regimens for small cell lung cancer remains to be established. We evaluated the efficacy and safety of the paclitaxel and ifosfamide (PI) combination chemotherapy salvage regimen in heavily pretreated small cell lung cancer (SCLC) patients. Thirty-five patients who had received more than two prior chemotherapy regimens were treated with PI chemotherapy. Paclitaxel (175 mg/m(2)) was administered on day 1 and ifosfamide (2500 mg/m(2)) on day 1-2 every 3 weeks. Thirty-three patients were available for treatment response evaluation. Median age was 63 years (range, 40-78) and Eastern Cooperative Oncology Group (ECOG) performance scores of 0/1/2 were 29.4%, 61.8%, and 11.8%, respectively. A median of 2 cycles (range, 1-6) of chemotherapy were administered. The overall response rate (RR) in the intent-to-treat population was 20.0% (95% Confidence Interval (CI), 6.7-33.3%) with 7 partial responses (PR) and no complete response (CR). Patients who responded to previous chemotherapy just before PI showed significantly higher RR than non-responders (RR, 57.1% versus 10.7%, P=.023). After a median follow-up of 8.8 months (range, 1.6-14.7), the median time to progression was 3.3 months (95% CI, 2.3-4.4) and the median overall survival was 7.6 months (95% CI, 6.7-8.5). The most common toxicity observed was mild nausea/vomiting and grade 3/4 adverse events were observed in 4 (11.4%) patients. There were no treatment-related deaths in the study. Our findings suggest that salvage PI chemotherapy is a feasible and well tolerated regimen for previously treated SCLC patients. Further studies are warranted to define the effects of PI chemotherapy on quality of life and survival benefits.