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The roots and rhizomes of Caulophyllum thalictroides (blue cohosh), traditionally used as an aid for childbirth, contain several active alkaloids and saponins, which act directly on uterine smooth muscle resulting in an oxytocic response. The historical use of this herbal supplement has been well documented, but there are few clinical studies addressing its efficacy and potential side effects. This research investigated the physiological and pharmacological responses of blue cohosh on isolated strips of murine uterine tissue. Uterine horns from mice were suspended in a smooth muscle bath and exposed to the aqueous extract of blue cohosh (doses ranging from 0.037–23.8 mg). All tissues showed an increase in the strength of contractile force, the frequency of the contraction, and basal tonus. Contractile forces were significantly greater with higher doses (P = 0.0027). The stages of estrous were determined by vaginal smears and dose-dependency was consistent in all stages of estrous observed (diestrus, estrus, metestrus). Blocking experiments with d-tubocuranine, a nicotinic receptor antagonist, were inconclusive as decreases in contractile responses were not statistically different from the observed fatigue following control cumulative dosing.