Hormone replacement therapy may protect against cardiovascular disease through several mechanisms that have variable actions on the major determinants of plasma viscosity. Plasma viscosity is an important predictor of incident and recurrent cardiovascular events and mortality in coronary heart disease patients. The effect of estrogen alone or in combination with progestin on plasma viscosity is not known. Using a randomized, double-blind design, we examined the impact of the following daily hormone regimens on plasma viscosity in 23 women: (1) 1 mg estradiol and 2.5 mg medroxyprogesterone (n=7); (2) 1 mg estradiol alone (n=8); and (3) placebo (n=8). Plasma viscosity, fibrinogen, and standard lipoprotein levels were determined at baseline and after 12 weeks of intervention. Plasma viscosity was measured at 37 degreesC with a coaxial microviscometer. Fibrinogen was measured by the Clauss method. Significant changes in plasma viscosity (mPa.s) levels occurred among treatment groups (P<0.01) after the intervention. Plasma viscosity was significantly reduced with estrogen replacement therapy (P<0.01). These data demonstrate that estrogen replacement therapy lowers plasma viscosity. This study suggests an additional mechanism for the cardiovascular protection conferred to postmenopausal women on estrogen replacement therapy.