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Summary: The inflammatory functions of the cytokine tumor necrosis factor (TNF) rely on its ability to induce cytokine production and to induce cell death. Caspase-dependent and caspase-independent pathways—apoptosis and necroptosis, respectively—regulate immunogenicity by the release of distinct sets of cellular proteins. To obtain an unbiased, systems-level understanding of this important process, we here applied mass spectrometry-based proteomics to dissect protein release during apoptosis and necroptosis. We report hundreds of proteins released from human myeloid cells in time course experiments. Both cell death types induce receptor shedding, but only apoptotic cells released nucleosome components. Conversely, necroptotic cells release lysosomal components by activating lysosomal exocytosis at early stages of necroptosis-induced membrane permeabilization and show reduced release of conventionally secreted cytokines. : Tanzer et al. provide a view of dynamically released proteins during TNF-induced apoptosis and necroptosis. The data highlight processes that are commonly and differentially regulated during these two different types of cell death. Keywords: necroptosis, apoptosis, cytokine release, lysosomal exocytosis, receptor shedding, TNF, mass spectrometry, extracellular vesicles