In order to determine whether there is a difference in the effect of the hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor pravastatin on cholesterol synthesis between the morning and the evening, we studied the 24-h profile of mevalonate in plasma and urine in 11 subjects with heterozygous familial hypercholesterolaemia. In study 1, eight subjects with familial hypercholesterolaemia took pravastatin (20 mg) once in the morning, and another 20-mg dose in the evening after a 1-week wash-out period. In study 2, five subjects with familial hypercholesterolaemia took pravastatin (20 mg per day) in the morning on 3 consecutive days and on 3 days in the evening after a 1 day wash-out. Plasma mevalonate concentrations were reduced at 9 h and 5 h after pravastatin administration in the morning and the evening, respectively. Urinary mevalonate excretion was significantly reduced at 4-8 h after pravastatin administration in the morning (51 vs 19 nmol'h 1) and at 4 16h after pravastatin administration in the evening (56vs 27 nmol' h ~). Daily urinary mevalonate excretion was equally and significantly reduced by pravastatin in the morning or evening. In conclusion, we found that morning and evening administration of pravastatin caused equal reductions in plasma and urinary mevalonate concentrations.