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 three patients suggested that approximately 50% of an orally administered dose was absorbed. Ten additional patients were randomized to receive either 100 mg/m2/day iv 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 curves (C X t) revealed that 17%-72% (mean, 52%) of an orally administered dose was absorbed. Absorption was less than 40% for only one patient. For oral and iv preparations, mean peak plasma VP-16 concentrations were 9.6 and 13.0 micrograms/ml, mean alpha-half-lives were 0.96 and 0.82 hour, mean beta-half-lives were 7.2 and 6.8 hours, mean C X t values were 75.9 and 75.3 mg/L/hour, mean plasma clearances were 1.44 and 1.45 L/hour/m2, and mean extrapolated volumes of distribution were 15.2 and 16.9 L/m2, respectively. The half-life for oral absorption was 0.44 hour and peak plasma concentrations were noted 0.5-3 hours after oral drug administration. Granulocyte count nadirs tended to be lower in patients with high C X t values and low plasma clearance values. Granulocytopenia was dose-limiting. Gastrointestinal toxicity was extremely mild. We recommend doses of oral VP-16 of 800 mg/m2/course over 3-5 days 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.