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In an attempt to develop more effective chemotherapy regimens in advanced nonsmall cell lung cancer (NSCLC), we evaluated docetaxel-ifosfamide-cisplatin (DIP) based on our previous experience with paclitaxel-ifosfamide-cisplatin. Patients with advanced NSCLC (stages III-IV), WHO-PS≤2, no prior chemotherapy and unimpaired hematopoietic and organ function were eligible. Chemotherapy was administered in successive dose levels (DLs) and included docetaxel (80–100 mg/m² day 1), ifosfamide (4–5 g/m²) and cisplatin (80–100 mg/m²), both divided over days 1 and 2 every 21 days. G-CSF (lenograstin) was administered from days 4–13. Fifty-five patients were accrued (phase I: 15; phase II: 40) and all are evaluable for response and toxicity: median age = 58 (40–72); PS = 1 (0–2); gender = 48 males, 7 females; stages IIIA = 8, IIIB = 19, IV = 28; and histologies were adenocarcinoma (29), squamous (20), large cell (6). Metastatic sites at diagnosis included lymph nodes (33), bone (8), liver (6), brain (6), lung nodules (9), adrenals (7) and soft tissue (1). The dose-limiting toxicity (DLT) was reached at DL4 (Docetaxel: 100 mg/m²-Ifosfamide: 5 g/m²-Cisplatin: 100 mg/m²) consisting of 2 cases of febrile neutropenia (FN), and DL3 (Docetaxel: 100 mg/m²-Ifosfamide: 5 g/m²-Cisplatin: 80 mg/m²) was considered as the maximum tolerated dose (MTD) and recommended for further phase II testing. Among evaluable patients in phase II, 31/46 (67%; CI = 54–81%) responded; 4 were complete responses, 27 partial responses, 12 with stable disease and 3 with progressive disease. The median response duration was 7 months (2–21+), median time to progression (TTP) 8 months (1–23+) and median overall survival (OS) 13 months (2–23+). The 1-year survival was 57%. Grade (Gr) 3/4 toxicities included neutropenia 39/46 with 27 developing Gr4 (≤7 days) and 20% FN managed successfully with broad-spectrum antibiotics, thrombocytopenia Gr3 3/46-Gr4 1/46, no Gr3 neuropathy, Gr1-2 CNS toxicity in 12, no renal toxicity, 15 Gr2 myalgias, 17 Gr2 diarrhea and 10 Gr3 vomiting. In the present phase I-II study, DIP appears highly active and tolerable in advanced NSCLC in the outpatient setting. Randomized comparisons to current standard 2-drug regimens will be warranted. © 2001 Wiley-Liss, Inc.