The effect of histamine on progesterone synthesis and cyclic adenosine 3’,5’-monophosphate (cAMP) accumulation was studied in superfused and incubated follicles dissected free from immature rats treated with pregnant mare serum gonadotrophin (PMSG). Histamine, like LH, increased the progesterone synthesis, but to a smaller extent. The H2-antagonist, cimetidine, inhibited completely the histamine-induced progesterone increase while the H1-antagonist, pyrilamine, as well as propranolol and atropine did not affect the initial response but modified its duration. The specific H2-agonist, 4-methyΓhistamine, but not the H1-agonist, 2-methylhistamine, mimicked the effect of histamine on progesterone synthesis. In the presence of the phosphodiesterase inhibitor, IBMX, histamine increased tissue levels of cAMP. These results suggest that histamine stimulates progesterone synthesis via the H2-receptor with cAMP acting as secondary intracellular messe