Despite advances in the modalities used to treat non-small cell lung cancer (NSCLC), the frequency of locoregional and distant relapses necessitates further enhancement of the therapeutic program. Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) has demonstrated clinical efficacy against NSCLC and in vitro studies support its role as a radiation potentiator at concentrations achievable in vivo. Thus, a phase I study of weekly paclitaxel and daily concurrent thoracic radiation was conducted in patients with advanced NSCLC to determine (1) the maximum tolerated dose of paclitaxel administered on an outpatient basis for 6 consecutive weeks with daily radiation and (2) the toxicities of the paclitaxel/radiation combination. Paclitaxel was administered as a 3-hour infusion, repeated weekly for 6 weeks with the usual premedication regimen for hypersensitivity prophylaxis. The starting dose of paclitaxel was 10 mg/m2/wk, which was increased by 10 mg/m2 in successive cohorts of three new patients, as tolerated. Radiation therapy was delivered as 40 Gy in 20 fractions to the original volume with a boost of 20 Gy in 10 fractions to the primary tumor. Doses were escalated from 10 to 70 mg/m2/wk. Of the 23 patients evaluable for response, one had stage II NSCLC, four had stage IIIA, 17 had stage IIIB, and one had stage IV. Severe esophagitis (grade 4) occurred in two of the three patients treated at 70 mg/m2 and was dose limiting. One patient discontinued therapy due to hypersensitivity, two developed grade 3 neutropenia, and one developed radiation pneumonitis. With a median follow-up of 7 months, 15 of the 23 patients remain alive. Four had a complete response and 13 had a partial response, for an overall response rate of 74% (95% confidence interval, 52% to 90%). The schedule of weekly paclitaxel and daily thoracic radiation appears active in NSCLC and can be delivered safely in the outpatient setting. The principal dose-limiting toxicity is esophagitis, and the maximum tolerated dose of paclitaxel for this schedule is 60 mg/m2/wk. A phase II trial of weekly paclitaxel 60 mg/m2 and radiation has been initiated in patients with NSCLC.