The disposition in the human body of the C14-labeled synthetic steroids (6α-methyl-17α-acetoxyprogesterone, 6α-methylprednisolone and prednisolone) was compared to that of 3 natural steroids (cortisol, 17α-hydroxyprogesterone and progesterone). The unconjugated steroid metabolites of cortisol, 17α-hydroxyprogesterone, progesterone and 6α-methylprednisolone were cleared from the plasma at a rate with a half-life of approximately 1.5 hours. In contrast, prednisolone and 6α-methyl-17-acetoxyprogesterone were cleared at a much slower rate (half-life of over 200 minutes). Glucosiduronates of the progesterone group of compounds reached high levels in the plasma within fifteen minutes after intravenous injection, in contrast to the low and slowly achieved levels of glucosiduronates reached by the cortisol group of steroids. Other differences between the two groups were: higher theoretical volume of distribution shown by the former, higher urinary excretion of the latter, and substantial biliary and fecal excretion of the progesterone group of steroids. The differences in clinical effectiveness and physiologic effects of the various steroids are apparently not explicable in terms of single factors, but are probably due to a number of differences involving various characteristics of their metabolism, including differences in the clearance from plasma, in biliary excretion and in the routes of metabolism of the administered steroids.