Abstract Autophagy is a catabolic process involved in cell death and in cell protective mechanism. Autophagic cell death is differentiated from apoptosis by the presence of double or multiple-membrane enclosed vesicles, and the ATG proteins are essential for the formation of these autophagic vesicles. Here, we show that ATG6/Beclin-1 is a novel caspase substrate. ATG6 is directly cleaved by caspases in a process inhibited by the pan caspase inhibitor, zVAD. Ectopic expression of ATG6 suppresses cell death while reduction of ATG6 levels by siRNA sensitizes cells to TRAIL-induced cell death. Also, the inhibition of caspases leads to an increase in autophagy. These results suggest that caspase-mediated cleavage of ATG6 links the apoptotic and autophagic signaling pathways.