Currently there are only a limited number of tools to assess endometrial receptivity. Given that the endometrium undergoes repeated proliferation and differentiation phases, we speculated that immunohistochemical examination of mitotic regulators, e.g. cyclins, might lead to a clinically useful method of identifying atypical, unreceptive endometrium. To evaluate the normal distribution of these markers, we analyzed endometrial biopsies from fertile women. Cyclin E (an activator of the mitotic G1 to S phase transition) and p27 (an inhibitor of cyclin E) immunohistochemistry was performed on endometrial biopsies collected from healthy parous women. 22 biopsies from 14 volunteers and 2 tubal ligation patients were collected from the mid-proliferative (MP) through the late secretory phases. All patients were 25-35 years old. Biopsies were fixed in formalin, paraffin embedded and immunohistochemically stained for cyclin E and p27. H&E sections were used for endometrial dating of the stroma and glands according to the criteria of Hendrickson and Kempson. Using the anti-cyclin E antibody we found: 1) MP glands exhibited strong basal and lateral cytoplasmic staining, 2) from CD 16 to 17 the cytoplasmic lateral staining decreased while the basal staining increased, 3) from CD 18 to 19 there was a reciprocal pattern of decreasing cytoplasmic and increasing nuclear staining, 4) CD 24 to 28 biopsies revealed only trace nuclear staining. Using the anti-p27 antibody we found: 1) there was trace nuclear staining in MP to CD 16 biopsies, 2) nuclear staining progressively increased from CD 17 to 19, 3) CD 24 to 28 endometria exhibited strong nuclear staining. These results demonstrate that the expression of cyclin E and P27 dramatically changes in intensity and subcellular localization throughout the menstrual cycle with cyclin E most highly expressed in the proliferative, estrogenic, phase and p27 most highly expressed during the luteal, progesterone, phase. We infer from the changes in subcellular distribution and concomitant nuclear appearance of these cell cycle regulators between CD 16-18 that the regulation of cyclin E and p27 may represent the mechanism by which estrogen and progesterone mediate proliferation and differentiation in the endometrium. Abnormalities in the expression of these markers may identify defects in endometrial development in a subset of women with unexplained infertility.