We studied the effects of two retinoids, naturally occurring all-trans-retinoic acid (retinoic acid) and the synthetic 4-hydroxyphenylretinamide (4-OH-PRT) on monolayer cultures of rabbit synovial fibroblasts and on explants of rabbit articular cartilage. Treatment of fibroblasts with phorbol myristate acetate (PMA; 10⁻⁸ M) induced the synthesis and secretion of large amounts of collagenase; this was inhibited if the cells were treated with retinoic acid (10⁻⁶ M) or dexamethasone (10⁻⁷ M). Combined treatment with retinoic acid and the steroid prednisolone, at concentrations as low as 10⁻¹⁰ M, gave an additive inhibition of collagenase production. Both retinoids inhibited collagenase production, but only 4-OH-PRT prevented the increase in prostaglandin E₂ (PGE₂) induced by PMA. Levels of plasminogen activator were also increased by treatment with PMA, and concomitant addition of either retinoid further enhanced this stimulation. Possible toxicity was assessed by measuring release of glycosaminoglycans (GAG) from explants of articular cartilage. Treatment with retinoic acid induced release of 80% of the total GAG, whereas treatment with 4-OH-PRT resulted in release of 40% of the total, a finding similar to that seen with untreated samples. 4-OH-PRT inhibited production of collagenase and PGE₂ by rabbit synovial fibroblasts but was not toxic to articular cartilage.