We investigated the effects of 17β-estradiol (βE 2 ), α-estradiol (αE 2 ), and progesterone (P) on baseline and vasopressin (AVP)-induced [Ca 2 + ] i in human platelets obtained from healthy male and female volunteers. Platelets were treated with βE 2 , αE 2 , P, or ethanol vehicle for 30 min at 37 o C. In males, both βE 2 and P at 10 - 5 mol/L reduced the AVP-induced rise in [Ca 2 + ] i , to 72 +/- 3% (mean +/- SEM) and 53 +/- 3%, respectively. However, at 10 - 6 mol/L only βE 2 had a significant effect (P < .02). In females, 10 - 6 and 10 - 5 βE 2 reduced the AVP response to 85.3 +/- 4.6% and 80.8 +/- 5.4% of control values, respectively. Progesterone (10 - 6 and 10 - 5 mol/L) reduced the AVP response to 83.8 +/- 5.1% and 60.3 +/- 2.0% of control values, respectively. The inactive estrogen αE 2 had no effect on basal or AVP-induced rise in [Ca 2 + ] i in either subject population, suggesting hormonal specificity. Neither βE 2 nor P affected baseline [Ca 2 + ] i in either population. Thus, by attenuating [Ca 2 + ] i responses in platelets, βE 2 and P may modulate platelet aggregation and atherosclerosis.