The effects of histamine and its analogs 2-(2-pyridyl) ethylamine (PEA) and 4-methylhistamine (4 MH) have been studied on uterine preparations obtained from estrogen-primed guinea pigs and rats. (1) Histamine and 4 MH, a specific H2-receptor agonist produced relaxation in estrogen-primed rat uterus, whereas these agonists produced contraction in the estrogen-primed guinea pig uterus. (2) PEA, a specific H1-receptor agonist produced contraction in the guinea pig uterus but had no effect on the rat uterus. (3) Metiamide blocked responses to histamine and 4 MH in the rat uterus, whereas mepyramine blocked responses to histamine and PEA in the guinea pig uterus. (4) Propranolol produced competitive antagonism with histamine in the rat uterus, whereas it had no significant effect on the histamine or PEA responses in the guinea pig uterus. (5) Reserpine pretreatment completely abolished the responses to histamine and 4 MH in the rat uterus but did not alter the response in the guinea pig uterus. (6) Our data suggest that in rat uterus only H2-receptors are present and they are indirectly through the release of noradrenaline. In the guinea pig uterus both H1- and H2-receptors are present and are excitatory and directly acting.