Excessive Reactive oxygen species (ROS) production by neutrophils drives necrotizing inflammation of small blood vessels in Anti-neutrophil cytoplasmic antibody (ANCA)–associated vasculitis (AAV). However, the mechanism responsible for the dysregulated ROS production remains uncharacterized. Here, the authors report the contribution of soluble CD95L to neutrophil activation and ROS production and show that sCD95L—exposed AAV neutrophils undergo Caspase-10 cleavage of OTULIN, LUBAC activation and downstream mitochondrion-dependent ROS production and propose targeting of CD95 signaling as a promising therapeutic strategy in AAV.