When six normal men took probenecid with ketoprofen in a two-treatment crossover study, steady-state plasma concentrations of ketoprofen and ketoprofen conjugates rose, but plasma protein binding of ketoprofen and urinary excretion of ketoprofen conjugates decreased. Probenecid decreased protein binding of ketoprofen by 28 +/- 7%, total ketoprofen clearance by 67 +/- 11%, clearance of unbound ketoprofen by 74 +/- 10%, clearance of unbound ketoprofen by conjugation by 91 +/- 5%, and renal clearance of ketoprofen conjugates by 93 +/- 4%. An apparent decrease (22 +/- 29%) in unbound ketoprofen clearance by mechanisms other than conjugation might have been established in a study of more than six subjects. Probenecid, which reaches plasma concentrations that approach 100 times those of ketoprofen or its conjugates, appears to inhibit both the conjugation of ketoprofen and the renal excretion of ketoprofen conjugates. An alternative explanation to inhibition of conjugation involves cumulation and subsequent hydrolysis of ketoprofen conjugates as a result of the renal action of probenecid. In addition to the advantages of obtaining simultaneous uricosuric and anti-inflammatory effects, there may be clinical kinetic advantages of administration of probenecid with ketoprofen, because the large interdose concentration swings of ketoprofen are then substantially reduced.