The effects of estrogen and progesterone domination, achieved by administering estrogen (E) and estrogen plus progesterone (E+P), on rat uterine reactivity to Ca2+ and to Ca2+ channel ligands (antagonist and activator) were compared. The inhibitory activities of nifedipine, diltiazem, and D 600 against K+ depolarization-induced responses were not significantly different between E- and E+P-dominated states in longitudinal or circular muscle preparations. Tonic responses were significantly more sensitive than phasic responses, but the rank orders of activity for a series of 14 antagonists were identical, suggesting the existence of a common structure–activity relationship which paralleled that seen previously in other smooth muscles. E+P-dominated uteri were slightly more sensitive to Ca2+ responses in K+ depolarizing media, but pA2 values for nifedipine, diltiazem, and D 600 inhibition were not significantly different in tissues from animals in either hormone-dominated state. Binding of [3H]nitrendipine did not differ between hormonal states. Responses to Bay K 8644 were larger in E+P-dominated uteri but the binding density was twofold greater in the E-dominated uterus. This study suggests that pathways of Ca2+ mobilization through potential-dependent Ca2+ channels in rat uterus are not significantly altered between E- and E+P-dominated environments.