The purpose of this study was to investigate the maximum tolerated doses, dose-limiting toxicities, efficacy, and pharmacokinetic profiles in the combination of irinotecan and paclitaxel. Eligibility criteria included age 75 years or younger, good performance status, adequate organ function, and unresectable non-small cell or extensive disease of small cell lung cancer. Irinotecan was administered on days 1 and 8 over 90 minutes, and paclitaxel was administered on day 8 over 3 hours after 90 minutes from the end of the irinotecan infusion. Irinotecan and paclitaxel were dose-escalated from 40 and 135 mg/m and repeated every 4 weeks. The authors also administered a higher dosage with preventive granulocyte colony-stimulating factor support from day 9. Thirty-one patients were assessed for toxicities and responses. Dose-limiting toxicities were neutropenia and febrile neutropenia. The dose of irinotecan 60 mg/m and paclitaxel 200 mg/m with preventive granulocyte colony-stimulating factor support was tolerable and suitable for a phase II trial. Nine of 25 (36%) patients with non-small cell and all six patients with small cell carcinoma achieved partial response. The areas under the concentration versus time curves of irinotecan and its metabolites on day 8 were significantly higher than on day 1. This combination therapy must be planned only after careful consideration of the drug-drug interaction.