Mammalian proprotein convertases (PCs) play an important role in folliculogenesis, as they proteolytically activate a variety of substrates such as the transforming growth factor-beta (TGF-β) superfamily. Proprotein convertase subtilism/kexin (PCSK) 6 is a member of the PC family and is ubiquitously expressed and implicated in many physiological and pathological processes. However, in human granulosa cells, the expression of the PC family members, their hormonal regulation and the function of PCs are not clear. Here, we find that PCSK6 is the most highly expressed PC family member in granulosa cells. Luteinizing hormone (LH) increased PCSK6 mRNA level and PCSK6 played an anti-apoptosis function in KGN. Knockdown of PCSK6 not only increased the secretion of activin A and TGF-β2 but also decreased the secretion of follistatin, estrogen and the mRNA levels of follicle-stimulating hormone receptor (FSHR) and P450arom. We also found that in the KGN human granulosa cell line, TGF-β2 and activin A could promote the apoptosis of KGN and LH could regulate the follistatin level. These data indicate that PCSK6, which is regulated by LH, is highly expressed in human primary granulosa cells of pre-ovulatory follicles and plays important roles in regulating a series of downstream molecules and KGN apoptosis.