We previously fine mapped a mouse atherosclerosis susceptibility locus on chr 2 via an intercross between AKR/J (atherosclerosis resistant) and DBA/2J (atherosclerosis sensitive) strains on the apoE-deficient background. The Zbp1 gene, encoding Z-DNA binding protein 1, is one of only 3 protein coding genes in the fine mapped locus. Prior mouse aorta single cell RNAseq shows Zbp1 expression in monocytes and macrophages > endothelial cells and fibroblasts. The ZBP1 protein plays a role in non-canonical necroptosis and inflammatory signaling. There are 2 mouse Zbp1 mRNA splice isoforms, long and short, which respectively generate a full-length protein and a C-terminal truncated isoform that is missing the RHIM domains required for necroptosis activity. Our prior RNAseq found ~2-fold higher Zbp1 expression in DBA/2 vs. AKR bone marrow macrophages (p=0.002), with a short to long isoform ratio of about 2.5. To determine if Zbp1 is an atherosclerosis modifier gene, we treated wildtype (WT) and Zbp1 knockout (K0) female and male mice at 6 weeks of age, both on the C57BL/6J background, with LDLr antisense oligos weekly for 16 weeks while feeding a western-type diet. Upon sacrifice at 22 weeks of age, body weight, liver weight, total cholesterol, and HDL-C were significantly reduced in KO vs WT male, but not female, mice (p= 0.005, 0.0003, 0.007, and 0.002, respectively (Figure). In both male and female mice, there were non-significant trends for reduced aortic root lesion area in KO vs. WT mice. The median necrotic lesion area was decreased in KO vs. WT females by 55%, but due to variation this was not significant. In males, median necrotic area was decreased by 83% (p=0.02, Figure). The % necrotic lesion area was decreased by 32% in female (not significant) and 67% in male (p=0.009) KO vs. WT mice (Figure). Thus, Zpb1 appears to be an atherosclerosis modifier gene that may function by increasing lesion necrosis, concordant with its known role in non-canonical necroptosis.