Etoposide is more active in small cell lung cancer when given over 5 days than as a single injection. To examine this concept further, we designed this Phase II study in NSCLC using continuous low-dose oral etoposide. We enrolled 19 patients with measurable disease and the standard eligibility criteria. 16 had no prior chemotherapy. Etoposide was given at a dose of 50 mg by mouth daily. The median duration of therapy was 63 days (14-212 days). Toxicity was mild myelosuppression and GI symptoms. Therapy was discontinued because of progression of disease in 13 patients, toxicity (GI) in 3 patients; intercurrent disease, self-removal, and other reasons in 1 patient each. No complete or partial responses were seen (95% CI: 0-17.6%). The median survival after entry into the trial was 159 days (41-571+ days). We conclude that low-dose continuous oral etoposide is a well-tolerated but ineffective regimen in non-small cell lung cancer.