Rates of alkaline hydrolysis of 18 natural or semisynthetic pyrrolizidine alkaloids, all retronecine diesters, have been compared. Steric hindrance around the ester groups was the major factor inhibiting hydrolysis. Relative rates of hydrolysis by esterases in a rat liver homogenate were also dependent on steric hindrance. However, in a series of less hindered esters with unbranched acids, hydrolysis rates increased with chain length to a maximum for the valeryl diester. Enzymic hydrolysis of retronecine di-isovalerate occurred primarily at the allylic 9-ester group. The results supported the view that a factor contributing to the lower hepatoxicity of semisynthetic retronecine diesters compared with some natural pyrrolizidine alkaloids, is their greater susceptibility to detoxication by hydrolysis.