Caspase-10 (also known as Mch4 and FLICE2) is an initiator caspase in the death receptor (DR)-dependent apoptotic pathway. So far six splice variants (caspase-10a-f) have been identified. Here we describe a novel isoform of the caspase-10 family named caspase-10g that is widely expressed in normal human tissues and various cell lines. Caspase-10g consists of 247 amino acids and does not contain the large or small subunit. A caspase-10g-specific exon is present between exon 5 and exon 6, which results in a protein product truncated shortly after the death-effector domain (DED)-containing prodomain. We further show that overexpression of caspase-10g dramatically enhances NF-kappaB activity in a dose- and time-dependent manner. Moreover, caspase-10g, unlike the protease-active caspase-10a, only promotes slight apoptosis when overexpressed in mammalian cells and it has no effect on caspase-10a-mediated apoptosis. Taken together, these results suggest that caspase-10g, as a novel prodomain-only isoform of caspase-10, may play a regulatory role preferentially in the NF-kappaB pathways.