We previously reported increased apoptosis in the maternal circulation during pregnancy, partly accounting for the presence of cell-free fetal DNA in maternal plasma. In the current study, apoptosis was quantitated in 60 peripheral blood samples obtained from 15 women sequentially tested postpartum using the binding of annexin V. FISH with X/Y probes was performed on annexin V-positive cells isolated by MACS in patients with male fetuses to estimate the proportion of fetal cells among the apoptotic cell population. Twenty-four women at the thirty-seventh to thirty-eighth week of gestation and 35 nonpregnant females were used as controls. Apoptosis rate in the thirty-seventh to thirty-eighth week was 12.5% (9.2-14.7%). At 30 minutes, 12 hours, 24 hours, and 48 hours postpartum, it was 25.1% (16.8-28.5%), 12.5% (10.9-14.1%), 6.1% (4.8-7.1%), and 2.3% (1.3-3.0%), respectively. Male apoptotic cells were identified in all cases with male fetuses at 37 to 38 weeks of gestation, and the mean proportion was 9.9% (5.9-13.2%). The proportion of fetal cells 30 minutes after delivery was 14.8% (12.5-25.5%) and 12 hours postpartum 2.1% (0.8-4.1%). Male fetal apoptotic cells were detected in three of eight samples collected 24 hours after delivery from women who delivered males, at frequencies of 0.10%, 0.15%, and 0.25% (mean 0.16%). There were no fetal apoptotic cells 48 hours after delivery. Apoptosis partly accounts for the clearance of fetal cells from the maternal circulation. Because it is a rapid reaction, completed within 2-3 hours, persistence of fetal cells is possibly due to apoptosis-resistant progenitors or to defective regulation of apoptosis, leading to fetal cell microchimerism associated with autoimmune diseases.