Some investigators have postulated that a constant low blood level might be the ideal mode of treatment while others have seen no reason to divide up the daily dose. To our knowledge this study is the first to include crossover of subjects to eradicate individual differences. Our aim was to compare the pharmacokinetic effects of administering etoposide three times a day vs. once a day as 25 mg capsules. Two groups of four patients each received 75 mg/day oral etoposide for 2 days either as 75 mg once daily or as 25 mg three times daily for 2 days. On days 8 and 9, the treatments were switched between groups. On the one-dose schedule, C-peak (peak plasma concentration) was greater than 2 mug/ml in live patients and greater than 3 mug/ml in three patients, while in none of the patients on the three-dose schedule did the peak exceed 2 mug/ml. No significant difference was found in terms of C-mean (calculated by dividing the area under the curve by the observed time) between the two treatments. Variability of blood concentrations of etoposide over a 24 h period was high on the one-dose schedule (median 95%, range 54-148%) but it was lower on the three-dose schedule (median 39%, range 28%-55%). No significant differences were found between the two different dosing schedules in terms of the median duration of etoposide blood levels above 0.5 mug/ml and above 1.0 mug/ml. These results suggest that detailed clinical toxicity and efficacy data are needed to ciarify the possible benefits of the fractionated administration of oral etoposide.