Recurrent spontaneous miscarriage (RSM) is a systemic disorder that has been defined as two or more pregnancies lost before the 20th week of gestation. Although the impaired function of macrophages at the maternal-fetal interface has been reported to be associated with RSM, the underlying mechanisms have not been fully elucidated. Here, we revealed that HDAC8 plays a critical role in RSM. Our results show that the mRNA and protein expression of HDAC8 was decreased in decidual macrophages from RSM patients. Moreover, the knockdown of HDAC8 resulted in a significant decrease in CD163 expression and an increase in apoptosis in dTHP-1 macrophages. Mechanistically, the ERK signaling pathway was activated in HDAC8-knockdown macrophages. When HDAC8-knockdown cells were pretreated with the ERK inhibitor U0126, expression levels of CD163, activated caspases 3, 7 and 9, and the apoptosis rate, were rescued. Taken together, our current results suggest that HDAC8 plays an important role in macrophage activation and apoptosis and may contribute to maintaining normal pregnancy by increasing the expression of M2 marker genes and inhibiting the apoptosis of macrophages at the maternal-fetal interface.Keywords: recurrent spontaneous miscarriage / decidual macrophages / THP-1 / HDAC8 / CD163.