Activation of cryopyrin induces cathepsin B–dependent rapid cell death of human THP-1 monocytic cells. Activation of cryopyrin is induced by the CAPS-associated mutation or R837. It induces necrosis-like cell death, which is accompanied by lysosomal leakage (ssΔLL) and loss of mitochondrial inner transmembrane potential (Δψm). All of these effects are effectively suppressed by the cathepsin B–specific inhibitor CA-074-Me, indicating that the cell death involves a cathepsin B–dependent pathway. Unfortunately, the mechanism of cathepsin B release into the cytosol upon activation of CIAS1 remains unclear; however, there may be an amplification pathway that cathepsin B participated in further lysosomal leakage upon activation of CIAS1. Activation of cryopyrin induces cathepsin B–dependent rapid necrosis-like cell death, which has the potential to evoke inflammation.