The effects of exogenous histamine (H) on prostaglandin (PG) generation and release in uteri isolated from diestrous rats and the influences of H 2-receptors blockers (cimetidine and mitiamide) on the output of uterine PGs, were explored. Moreover, the action of H on the uterine 9-keto-reductase, was also studied. Histamine (10 −4M) failed to alter the basal output of PGE 1 but reduced significantly the generation and release of PGE 2 and augmented the output of PGF 2α. On the other hand, cimetidine (10 −5M) enhanced the basal release of PGE 2 but had no action on the outputs of PGs E 1 or F 2α. The enhancing effect of H on the production and release of PGF 2α was abolished in the presence of cimetidine. Also, the antagonist reversed the influence of H on the output of PGE 2. Metiamide, another H 2-receptor antagonist, did not alter the basal control generation and release of uterine PGs, but antagonized the augmenting influence of H on PGF 2α uterine output, as much as cimetidine did, and prevented the depressive action of H on the release of PGE 2 from uteri. Histamine (10 −4M) significantly stimulated uterine formation of cyclic-adenosine monophosphate, an action which was antagonized by the presence of cimetidine (10 −5M), a blocker of H 2 receptors. Also, histamine (10 −5M) and dibutyril-cyclic-adenosine monophosphate (DB-cAMP) at 10 −3M, enhanced significantly the formation 3H-PGF 2α from 3H-PGE 2. Results presented herein demonstrate that H is able to diminish the generation of PGE 2 in uteri from rats at diestrus augmenting the synthesis of PGF 2α, apparently via the activation of H 2-receptors, enhancing adenylate-cyclase. These effects appear to increase uterine 9-keto-reductase activity which transforms PGE 2 into PGF 2α. Relationships between the foregoing results and those evoked by estradiol, are also discussed.