The role of female sex hormones in the pathogenesis of gallstones is well established. Pregnancy, contraceptive use, estrogen replacement therapy in postmenopausal women, and estrogen therapy in men for the treatment of prostatic carcinoma have been found to be associated with increased risk of cholesterol gallstones. Alterations in gallbladder emptying and in bile lithogenicity in postmenopausal women receiving hormone replacement therapy (HRT) have not been studied to date. The present study was undertaken to study the effect of HRT on gallbladder emptying and bile lithogenicity. Sixteen postmenopausal women were included in the study. None of the patients had gallstone disease and none had received prokinetic drugs, such as, erythromycin, metoclopramide, domperidone or cisapride, aspirin, and nonsteroidal antiinflammatory drugs. Gallbladder emptying (n = 16), bile microscopy (n = 7), cholesterol saturation index (CSI) (n = 7), and nucleation time (n = 7) were studied before and 3 months after HRT (conjugated estrogen, 0.625 mg, + medroxyprogesterone acetate, 2.5 mg, everyday). Fasting and residual volumes increased (fasting volume, 18.2 +/- 2.2 mL pre-HRT vs 27.6 +/- 3.2 mL post-HRT, P = 0.0003; residual volume, 3.9 +/- 0.6 mL pre-HRT vs 10.3 +/- 2.0 mL post-HRT, P = 0.00009) and ejection fraction decreased (78.2 +/- 2.5% pre-HRT vs 62.2 +/- 3.8% post-HRT; P = 0.0017) after 3 months of HRT. There was no change in CSI (2.32 +/- 0.36 pre-HRT vs 2.60 +/- 0.51 post-HRT; P = NS) or in nucleation time (19.0 +/- 1.2 days pre-HRT vs 17.6 +/- 1.3 days post-HRT; P = NS). None of the bile samples either pre-HRT or post-HRT showed cholesterol monohydrate crystals. Though impairment of gallbladder emptying occurs in the short term with HRT in postmenopausal women, there is no change in CSI and nucleation time.