The pharmacokinetics of ibuprofen are complicated by the unidirectional metabolic inversion of the (-)-R- to (+)-S-enantiomer. Chiral inversion is of therapeutic significance since the drug's pharmacologic activity has been shown to depend upon the (+)-S-isomer. As a result, the present study was undertaken to determine if chiral inversion occurs systemically and to elucidate further the kinetics of the inversion process. Experiments were performed in the beagle dog after intravenous bolus injections of ibuprofen enantiomers separately [100 mg (-)-R, n = 4; 100 mg (+)-S, n = 4] and as admixtures of varying proportions [100 mg (-)-R + 100 mg (+)-S, n = 4; 100 mg (-)-R + 200 mg (+)-S, n = 2]. Plasma samples of (-)-R- and (+)-S-enantiomers were measured by a stereospecific HPLC assay after all drug administrations. Based on the area under the plasma concentration-time curves for (+)-S after administration of each enantiomer alone, chiral inversion was 70 to 75%. A progressive reduction in total plasma clearance of (-)-R-ibuprofen is also observed as increasing amounts of (+)-S-enantiomer are added to the system. The results demonstrate that chiral inversion occurs to a significant extent in the systemic circulation in dog and that R-to-S inversion of ibuprofen may be inhibited by its (+)-S-enantiomer.