Macrophage dysfunction in obesity and diabetes may predispose to the development of diabetic complications, such as infectionand impaired healing after tissue damage. Saturated fatty acids, such as palmitate, are present at elevated concentrations in theplasma of patients with metabolic disease and may contribute to the pathogenesis of diabetes and its sequelae. To examine theeffect of lipid excess on macrophage inﬂammatory function, we determined the inﬂuence of palmitate on LPS-mediated responsesin peritoneal macrophages. Palmitate and LPS led to a profound synergistic cell death response in both primary and RAW 264.7macrophages. The cell death had features of apoptosis and necrosis and was not dependent on endoplasmic reticulum stress,ceramide generation, or reactive oxygen species production. Instead, we uncovered a macrophage death pathway that requiredTLR4 signaling via TRIF but was independent of NF-kB, MAPKs, and IRF3. A signiﬁcant decrease in macrophage lysosomalcontent was observed early in the death pathway, with evidence of lysosomal membrane damage occurring later in the deathresponse. Overexpression of the transcription factor TFEB, which induces a lysosomal biogenic program, rescued the lysosomalphenotype and improved viability in palmitate- and LPS-treated cells. Our ﬁndings provide new evidence for cross-talk betweenlipid metabolism and the innate immune response that converges on the lysosome.