OBJECTIVE Our purpose was to evaluate the mechanisms of cocaine's effect on both spontaneous and agonist-induced contractility of pregnant human myometrium. METHODS Myometrium was obtained from 42 women at term who were undergoing cesarean section. Myometrial strips were suspended in contraction baths and isometric contractions were measured. Tissue was exposed to various combinations of cocaine, prazosin, desipramine, benzoylecgonine, and procaine. Spontaneous contractility and the contractile responses to increasing concentrations of methoxamine and oxytocin were measured and compared. RESULTS Cocaine increased spontaneous myometrial contractility by more than threefold. Prazosin, an alpha-adrenergic antagonist, blocked this effect only for the first 35 minutes of exposure. The cumulative concentration-response to the alpha-adrenergic agonist methoxamine was increased by cocaine in terms of both sensitivity and maximal response. The maximal response to oxytocin, but not the sensitivity, was increased by cocaine by an effect that could not be blocked by prazosin. CONCLUSIONS Cocaine augments spontaneous and agonist-induced contractility of pregnant human myometrium by mechanisms that appear to be both alpha-adrenergic and nonadrenergic in nature.