We assessed the efficacy and toxicity of two etoposide infusional schedules in patients with advanced non-small cell lung cancer (NSCLC). Twenty-six patients were treated with a 21 day infusion every 28 days at a dose of 25-40 mg/m2/d, and six patients with a 7-day infusion every 21 days at a dose of 45-75 mg/m2/d. Sixty-three percent of patients had a Karnofsky status of 80% or better, and only five (15%) patients had prior chemotherapy. Plasma etoposide concentrations were determined in 26 patients. Sixty-nine treatment cycles were administered. Two patients (6.3%; 90% confidence interval, 1.1-18.4%) had partial responses; with response durations of 2 and 7 months, respectively. The median survival was 4 months. Grade 3 or 4 neutropenia occurred in 13 of 69 cycles (19%) and was associated with three toxic deaths. Ten patients required RBC transfusions. Nausea was common, but was associated with vomiting in only 7% of all cycles. The interpatient variability of etoposide concentrations at steady state was significant. We conclude that the antitumor activity of prolonged infusion of etoposide is not superior to standard dose and schedule in advanced NSCLC.