The inotropic and chronotropic effects of histamine on the isolated perfused guinea pig heart were antagonized by promethazine over a concentration range 4 × 10−6 – 16 × 10−6 M. Promethazine (4 × 10−6 M) decreased the ability of histamine (1 μg) to elevate cardiac cyclic AMP. A higher dose of histamine could not overcome the promethazine blockade. Promethazine (4 × 10− 6 M) did not block the inotropic effect of noradrenaline. Higher concentrations of promethazine, particularly 16 × 10−6 M did decrease the noradrenaline response. The data indicate that promethazine can interact with cardiac histamine receptors but the interaction is either noncompetitive or competitive non-equilibrium in nature.