Lovastatin, widely used to lower cholesterol, is a pro-drug that requires metabolic activation through hydrolysis by carboxyesterases. There appear to be at least three distinct esterases in humans capable of catalysing this reaction, one in plasma and two in the liver. The rate of lovastatin hydroxy acid formation was measured as 15.8 pmol.ml-1.min-1 in plasma, 2.13 pmol.mg-1 protein.min-1 in hepatic microsomes and 0.92 pmol.mg-1 protein.min-1 in cytosol. The data suggest that on average the three esterases together are capable of activating about 220 nmol (90 micrograms) lovastatin per minute per person, to which the esterases of plasma, liver microsomes and liver cytosol contribute approximately 18, 15 and 67%, respectively. All three esterases showed evidence of inter-individual variability. In one of 17 livers, both cytosolic and microsomal esterase activity was completely missing, while two other liver specimens lacked one esterase. Such variability must be expected to influence the therapeutic efficacy of the drug, and they might be related to its occasional toxicity.