Hormone replacement therapy (HRT) remains the most effective treatment for menopausal symptom relief, and may provide cardiovascular benefits in younger women initiating treatment soon after menopause. However, large surveys indicate that many symptomatic women refuse or discontinue HRT prematurely owing to fear of weight gain. A continuous combined HRT containing 17beta-estradiol (E(2)) 1 mg plus drospirenone (DRSP) 2 mg is effective in relieving menopausal symptoms and preventing postmenopausal osteoporosis. DRSP is a unique synthetic progestogen with a pharmacological profile similar to that of natural progesterone, including antialdosterone activity, a property not exhibited by other synthetic progestogens. DRSP can therefore reduce estrogen-related sodium and water retention in postmenopausal women receiving HRT via the renin-angiotensin-aldosterone system, which regulates sodium and water balance. This may translate into weight benefits. Pooled data from two placebo-controlled clinical trials (n = 333) indicated statistically significant weight loss of -1.5 kg at 6 and 12 months in postmenopausal women receiving E(2)/DRSP vs. placebo (p < 0.001). In a third randomized controlled trial (n = 1147), women receiving E(2)/DRSP maintained or lost weight, whereas weight increases were observed in women receiving E(2) monotherapy (p < 0.0125). E(2)/DRSP could help maintain or even slightly decrease body weight during treatment, potentially improving HRT acceptance and compliance.