We conducted a prospective phase II study to determine the response rate, toxicity profile, and survival rate among patients with locally advanced unresectable non-small cell lung cancer receiving concurrent weekly paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ), carboplatin, and hyperfractionated radiation therapy followed by two cycles of adjuvant paclitaxel and carboplatin. The weekly paclitaxel/carboplatin regimen was designed to optimize the radiosensitizing properties of paclitaxel during the concurrent phase of treatment. Thirty-two patients with unresectable stage IIIA and IIIB non-small cell lung cancer from Vanderbilt Cancer Center Affiliate Network institutions entered the study from June 1996 until February 1997. Weekly intravenous paclitaxel (50 mg/m2 over 1 hour) and weekly carboplatin (area under the concentration-time curve of 2) plus concurrent hyperfractionated chest radiotherapy (1.2 Gy twice daily [69.6 Gy total]) delivered for 6 weeks were followed by two cycles of paclitaxel (200 mg/m2) and carboplatin (area under the concentration-time curve of 6). Among 22 patients evaluable for response, one (4.5%) achieved a complete response and 16 (72.7%) achieved partial response, for an overall response rate of 77%. Among 23 patients evaluable for toxicity, esophagitis was the principal finding: grade 3 or 4 esophagitis occurred in eight patients (35%). Grade 3 and 4 pulmonary toxicities each occurred in 26% of patients. Thus, weekly paclitaxel/carboplatin plus concurrent hyperfractionated radiotherapy is a well-tolerated outpatient regimen with an encouraging response rate that is at least equivalent to more toxic chemoradiation regimens. These findings indicate that further clinical evaluation of weekly paclitaxel/carboplatin/hyperfractionated radiotherapy is warranted in phase III trials.