Postmenopausal women are prescribed a standard dose of estrogen, which is optimal for a population but not for all individuals. We wished to identify if an individual's estradiol level can indicate the minimum effective dose of estrogen which maximally increases high-density lipoprotein (HDL) levels, which could be cardioprotective. We performed a prospective, double-blind crossover study in 19 healthy postmenopausal women, receiving three treatments in random order for 9 weeks each: a) placebo, b) 1 mg oral estradiol daily, and c) 2 mg oral estradiol daily. Lipoprotein and estradiol (E2) levels were measured 10-12 h after pills were taken. E2 levels with 1 mg estradiol were positively correlated with the increases in HDL levels (r = 0.70, P < 0.01). Only the eight subjects who had E2 levels < 50 pg/mL after 1 mg estradiol treatment demonstrated further increases in HDL levels by increasing the daily dose to 2 mg (by 3 +/- 5% with 1 mg estradiol and by 13 +/- 7% with 2 mg). The other 11 subjects who had E2 levels > 50 pg/mL with 1 mg estradiol had no additional benefit from increasing the estradiol dose (HDL increased by 13 +/- 9% with 1 mg, and by 17 +/- 10% with 2 mg). Thus, measurement of an E2 level the morning after taking 1 mg estradiol at bedtime identifies who may benefit from improvement in HDL levels by increasing to a 2-mg dose.