Bioavailability of an oral preparation of the antineoplastic drug etoposide (VP-16) was studied in 13 patients with advanced malignancies. An initial pilot study involving 3 patients suggested that approximately 50% of an orally administered dose was absorbed. Ten additional patients were randomized to receive either 100 mg/m2/day i.v. or 200 mg/m2/day orally. Three weeks later, the alternate dose schedule was administered. Plasma samples were assayed for VP-16 using a high-pressure liquid chromatography technique. Comparison of the area under concentration-time curve (C .times. t) revealed that 17%-72% (mean, 52%) of an orally administered dose was absorbed. Absorption was < 40% for only 1 patient. For oral and i.v. preparations, mean peak plasma VP-16 concentrations were 9.6 .mu.g/ml and 13.0 .mu.g/ml, mean .alpha.-half-lives were 0.96 h and 0.82 h, mean .beta.-half-lives were 7.2 h and 6.8 h, mean C .times. t values were 75.9 .mu.g/L/h and 75.3 mg/L/h, mean plasma clearances were 1.44 L/h/m2 and 1.45 L/h/m2 and mean extrapolated volumes of distribution were 15.2 L/m2 and 16.9 L/m2, respectively. The half-life for oral absorption was 0.44 h and peak plasma concentrations were noted 0.5-3 h after oral drug administration. Granulocyte count nadirs tended to be lower in patients with high C .times. t values and low plasma clearance values. Granulocytopenia was dose-limiting. Gastrointestinal toxicity was extremely mild. Doses of oral VP-16 of 800 mg/m2/course over 3-5 days is recommended for patients with a moderate amount of prior treatment. It is probable that previously untreated patients will tolerate a higher dose and that heavily pretreated patients will require a lower dose.