BACKGROUND To evaluate the activity of a nonplatinum-, nonetoposide-containing regimen for patients with extensive stage small cell lung cancer. METHODS Patients with untreated extensive stage small cell lung cancer were treated with gemcitabine 1000 mg/m2 and irinotecan 100 mg/m2 on days 1 and 8 of a 21-day cycle for a maximum of six cycles. Patients with brain metastases were eligible if asymptomatic or controlled after radiation. RESULTS Eighty-four eligible patients with untreated extensive stage small cell lung cancer with adequate organ function and a performance status of 0-2 were accrued. The median age was 64 years (range, 42-85) and 45 (54%) were women. Six cycles were completed by 28 (33%) patients. Some degree of diarrhea occurred in 57% (grade 3/4, 18%). Other grade 3/4 toxicities were neutropenia (26%), anemia (10%), thrombocytopenia (8%), febrile neutropenia (5%), fatigue (11%), nausea (10%), and vomiting (8%). The response rate was 32% (95% confidence interval: 22%-43%) among the 81 patients with measurable disease. The median survival was 8.5 months (95% confidence interval: 7.0-9.8) with 1- and 2-year survival rates of 26% and 7%, respectively. Salvage therapy data were captured by prospective collection, and only 50% of patients were treated secondarily. CONCLUSIONS The overall response rate with the combination of gemcitabine and irinotecan was disappointing, and the median survival rate was lower than expected. Further development of this combination in small cell lung cancer is not recommended.