Plasma, urine and CSF etoposide concentrations were measured in 12 adult patients after administration of high-dose (400-800 mg/m2) etoposide to determine the pharmacokinetics of this drug at these elevated dosages. Increasing the drug dosage produced proportionally higher peak plasma etoposide concentrations (27-114 .mu.g/ml) and total areas under the concentration-time curve (9200-48,000 .mu.g/ml .cntdot. min). The etoposide mean (.+-. SD) terminal half-life of 8.05 .+-. 4.3 h and plasma clearance of 28.0 .+-. 9.7 ml/min per m2, were independent of the dosage given. The mean etoposide renal clearance in 5 patients was 10.0 .+-. 4.3 ml/min per m2, representing from 35-40% of the total clearance of this drug from plasma. CSF etoposide concentrations ranged from 0.1-1.4 .mu.g/ml, as measured in 6 patients at 1-8 h after high-dose etoposide therapy, and were 1.8 .+-. 1.7% of the simultaneously measured plasma levels. Pleural fluid removed from 1 patient at 18 h posttherapy contained etoposide at 1.8 .mu.g/ml. The pharmacokinetics of high-dose etoposide is linear within the dosage range tested and similar to that seen with lower drug doses. They also suggest that etoposide penetrates poorly into the CSF.