After an intra-articular administration of methylprednisolone acetate (MPA) in the cow, methylprednisolone (MP) was detected in the synovial fluid, at pharmacologically significant concentrations, during more than 3 months. From in vitro assay, it was shown that hydrolysis of MPA to MP was rapid both in blood (half-times from 11.8 to 21.7 min) and in synovial fluid (half-times from 45.6 to 130.3 min). After intra-articular administration of MPA as a suspension (200 mg in toto), both MP and MPA decline very rapidly and, 24 hr after injection, less than 1% of the dose was present in the synovial fluid, but systemic availability of MP during the first 24 hr was only 30% of the dose. Twenty-four hours postadministration, post-mortem examinations showed a significant quantity of MPA precipitated at the bottom of the synovial cavity. It was assumed that the relatively slow decline of MP synovial fluid concentration from 24 hr to 5 days postadministration was due mainly to a process of MP absorption. After this delay, the synovial fluid concentration decreased very slowly with an apparent half-time of 18 days. This has been tentatively explained in terms of a slow release of MP from MPA embedded in a fibrin-like deposit. Despite the fact that the quantity of MP absorbed each day was small, long-term systemic effects were observed. During 6 weeks, plasma hydrocortisone levels remained low or undetectable and the return to normal adrenal responsiveness to an adrenocorticotropic hormone test took 12 weeks.