To elucidate the role of apoptotic cell death in human corpus luteum (CL) regression, human CL during the menstrual cycle and early pregnancy were isolated and processed for biochemical (radio-labeling) analysis of DNA integrity. Total DNA extracted from human CL of the early luteal phase contained predominantly high mol wt DNA, whereas CL of the midluteal phase exhibited the appearance of DNA cleavage into low mol wt ladders characteristic of apoptosis. Although apoptotic DNA cleavage of human CL significantly increased from the midluteal phase to the late luteal phase (P < 0.05), CL of early pregnancy did not exhibit apoptotic DNA fragmentation by biochemical analysis. In situ analysis of DNA fragmentation revealed that both large and small luteal cells exhibited DNA cleavage in human CL of the midluteal and late luteal phases and in regressive CL. The present findings suggest that 1) human luteal regression may be mediated by apoptosis; and 2) CL of early pregnancy may be rescued from luteolysis through inhibiting the occurrence of apoptotic luteal cell death.