Large randomized studies have shown superior survival results for sequential chemoradiotherapy compared with radiation alone in stage III non-small cell lung cancer. Similarly, chemotherapy followed by surgery was associated with longer survival than surgery alone in small randomized trials. Despite these results, disease recurs in most stage III patients. To improve these results, we are studying escalating doses of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) combined with platinum/etoposide and simultaneous thoracic irradiation as preoperative and curative therapy. Initially, paclitaxel was given at a starting dose of 35 mg/m2 intravenously (i.v.) over 24 hours on days 1 and 8; carboplatin (area under the concentration time curve) 4 mg/mL.min) i.v. was given on day 2 and etoposide 5 mg/d orally on days 1 to 5 and 8 to 12; cisplatin 50 mg/m2 i.v. was given on day 23, and radiation 2 Gy was given on days 1 to 5 and 8 to 12. Courses were repeated every 28 days. Four of five patients treated at the second paclitaxel dose level (90 mg/m2) experienced grade 4 toxicity. The treatment regimen was changed to paclitaxel given at a starting dose of 80 mg/m2 i.v. over 3 hours on day 1, carboplatin (area under the concentration time curve 4 mg/mL.min) i.v. given immediately after paclitaxel, etoposide 40 mg/m2 i.v. given over 1 hour on days 2 to 5, and radiation 2 Gy given on days 1 to 5 and 8 to 12. No grade 4 toxicity was observed in five patients treated at the first paclitaxel dose level (80 mg/m2). After two courses, pulmonary resection (lobectomy and pneumonectomy) was performed without fatalities in five patients. Although more data are needed, pulmonary resection appears feasible following treatment with this paclitaxel-containing regimen. Patient accrual is continuing to determine the maximum tolerated dose of paclitaxel.