Death receptor-mediated signaling pathways must be tightly regulated to ensure tissue homeostasis. In a previous study, ADAM15 was identified as a possible TNF-regulated protease. We here unveil ADAM15 as a regulator of TNF-mediated necroptosis, while apoptosis and survival pathways remain unaffected. ADAM15 knockout results in the modulation of death-associated proteins and protein networks. Using a bottom-up proteomics screen to compare human U937 wild-type and ADAM15 knockdown cells enabled us to identify proteins and networks affected by ADAM15 loss, and which may be involved in necroptosis regulation.