Plasma concentrations of free and total prednisolone were measured after oral doses at four time points to investigate the possibility of a diurnal variation in the drug's kinetics. There were marked differences in plasma prednisolone concentrations, clearance rates, and bioavailability of both free and total fractions at different times of the day. Changes in the protein binding characteristics of prednisolone with clock time resulted in marked differences between the kinetics of free and total prednisolone. It is recommended that for maximum efficacy and minimum toxicity prednisolone therapy be confined to once-daily dosing in the morning.