Macrophage apoptosis contributes to the formation of necrotic cores in atherosclerotic plaques, increasing the risk of plaque rupture, leading to clinical heart attack. Previous work from our group showed that HDL is able to protect macrophages against apoptosis, and that such protection requires HDL’s receptor protein scavenger receptor class B, type I (SR-BI). In this study, we hypothesize that this protection requires not only SR-BI, but also SR-BI’s adaptor protein PDZK1. We incubated mouse peritoneal macrophages with or without lipoproteins and triggered apoptosis with thapsigargin or tunicamycin. Cell apoptosis was assessed by annexinV, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and cleaved caspase-3 staining. Only low levels (~5% of cells) of apoptosis were observed in macrophages treated with thapsigargin or tunicamycin when they were cultured with lipoproteins. However thapsigargin or tunicamycin stimulated apoptosis increased ~4 fold when lipoproteins were removed from the culture medium. The addition of 50μg/ml of purified HDL (P<0.05), but not LDL, to lipoprotein-deficient medium suppressed apoptosis. However, HDL did not inhibit cell apoptosis when PDZK1 was deleted. Our time-course study showed that incubation with HDL increased phosphorylation of Akt1, Foxo3a and Erk1/2 and reduced Bim in wild type (WT), but not PDZK1-/- macrophages. In order to test the role of PDZK1 in vivo, LDLR-/- mice were transplanted with either PDZK1-/- (n=12) or WT (n=12) bone marrow and challenged with high fat diet to induce atherosclerosis. The cross-sections of aortic sinus were stained with H&E to visualize plaques. The relative necrotic core area was significantly larger (P<0.05) in PDZK1-/- group (98187.2±8076.1) than that in WT control (27279.6±16688.7). Also, compared to LDLR-/- mice transplanted with WT bone marrow, the ones with PDZK1-/- bone marrow have 2.2-fold increased TUNEL(+) (P<0.05) and 3.6-fold increased cleaved caspase-3(+) (P<0.01) macrophages in plaques. In conclusion, PDZK1 is required for the HDL-dependent protection against macrophage apoptosis. In atherosclerotic plaques, PDZK1 plays a role in protecting macrophages from apoptosis and suppressing the development of necrotic cores.