Ewes were treated systemically during the periovulatory period with the antihistamines diphenhydramine (H1-receptor antagonist) and(or) cimetidine (H2-receptor antagonist). None of the treatments prevented ovulation. However, the combination of drugs inhibited subsequent function of the corpus luteum (CL) as assessed by serum measurements of progesterone. Administration of antihistamines did not alter pituitary secretion of LH. Injection of small quantities of diphenhydramine and cimetidine into the antrum of the preovulatory follicle also caused aberrant luteal activity, but no blockade of ovulation. Intrafollicular injection of histamine reversed the inhibitory influence of antihistamines on the CL. Antihistamines suppressed preovulatory thecal edema and antral influx of plasma transudate containing LH. Thus, the effects of antihistamines appear to have been exerted at the follicular level. Function of matured CL was not compromised by peripheral administration of antihistamines. Actions of histamine within the preovulatory ovine follicle do not appear to be a prerequisite for ovulation, but apparently do have an impact on ensuing luteal function. We propose that a hyperemic reaction to histamine in preovulatory follicles enhances vascular filtration of LH. As a consequence, maximal permeation of the avascular granulosal layer of the follicle by LH leads to a normal luteinization response.