Long chain esters of cortisol have shown prolonged anti-inflammatory activity in both clinical and animal studies. This effect has been ascribed to the decreased water-solubility of the higher esters, but an alternative explanation is that the higher esters are hydrolysed more slowly to free steroid by the synovial tissue enzymes. In order to investigate the influence of chain length on hydrolysis rate we synthesized a series of cortisol 21-esters. When incubated in a 0.1% (w/v) homogenate of inflamed rabbit synovial tissue the esters with chain lengths of 4, 6, 8 and 10 carbon atoms were hydrolysed much faster than those with 2, 12, 14 and 16 carbon atoms. At tissue concentrations of 10% (w/v), however, the breakdown of cortisol acetate was greatly accelerated, whereas cortisol palmitate remained quite stable. Although cortisol esters were hydrolysed in 50% (v/v) rheumatoid synovial fluid, the rates of hydrolysis were relatively slow. The chain length dependence was similar to that seen with the tissue homogenate.