Simvastatin, a derivative of lovastatin, is a potent inhibitor of cholesterol biosynthesis and may interfere with steroid hormone production, for which cholesterol is required. In a single-blind, placebo-controlled study, 24 patients with severe primary hypercholesterolaemia (mean serum cholesterol +/- SD = 10.74 +/- 1.59 mmol/l) were treated with simvastatin 40 mg per day for 8 weeks. Before and after treatment, the following parameters were evaluated: basal levels of ACTH, cortisol, androstenedione, dehydroepiandrosterone and 17-hydroxyprogesterone; urinary excretion of free cortisol; the cortisol response after short-term infusion of ACTH; the ACTH and cortisol response during insulin-induced hypoglycaemia. Total serum cholesterol decreased by 35.0 +/- 8.1% (P less than 0.001) and low-density lipoprotein (LDL) cholesterol by 39.8 +/- 9.8% (P less than 0.001); high-density lipoprotein (HDL) increased by 9.2 +/- 11.1% (P less than 0.001). Basal levels of ACTH were higher after simvastatin (2.9 +/- 1.9 pmol/l vs 4.1 +/- 2.9 pmol/l; P less than 0.05) whereas basal levels of steroid hormones were not significantly changed. The excretion of free cortisol was unaltered. The peak cortisol after ACTH infusion was lower after treatment (0.87 +/- 0.23 mumol/l vs 0.78 +/- 0.10 mumol/l; P less than 0.05), but was unaltered during insulin-induced hypoglycaemia. We conclude that simvastatin lowers serum cholesterol without clinically relevant effects on the adrenocortical steroid hormone secretion and the hypothalamic-pituitary-adrenal axis.