This study was initiated to investigate the significance of uterine cell death and proliferation during the estrous cycle and early pregnancy and their correlation with sex steroids in hamsters where blastocyst implantation occurs in only progesterone-primed uteri. The results obtained in hamsters were also compared with mice where blastocyst implantation occurs in progesterone-primed uteri if estrogen is provided. Apoptotic cells in the uterus were detected by using terminal deoxynucleotide transferase (TdT)-mediated deoxyuridine triphosphate (dUTP) nick end labeling (TUNEL) technique. Uterine cell proliferation was determined by 5-bromo-2'-deoxyuridine (BrdU) labeling followed by immunohistochemistry and methyl-tritiated (³H)-thymidine labeling. Active caspase-3, an executor protein of cell death, expression was assayed by immunohistochemistry/Immunofluorescence. Our results demonstrate that epithelial proliferation on the second day after mating marks the initiation of pregnancy-related uterine changes in both species despite their differences in hormonal requirements. Hamsters and mice showed subtle differences in uterine proliferative and apoptotic patterns during early pregnancy and in response to steroids. There existed almost a direct correlation between apoptosis and caspase-3 expression suggesting uterine cell death mostly involves caspase pathway. Consistent with these findings, we showed, for the first time, that execution of uterine epithelial cell apoptosis by caspase-3 is important for blastocyst implantation since a caspsase-3 inhibitor Ac-DEVO-CHO when instilled inside the uterine lumen on day 3 of pregnancy inhibits implantation in hamsters and mice. The overall results indicate that uterine cell apoptosis and proliferation patterns are highly ordered cell-specific phenomena that play important role in maintaining sexual cycle and pregnancy associated uterine changes.