AbstractCellular lipid metabolism, lipoprotein interactions, and liver X receptor (LXR) activation have been implicated in the pathophysiology and treatment of cancer, although findings vary across cancer models and by lipoprotein profiles. In this study, we investigated the effects of human‐derived low‐density lipoproteins (LDL), high‐density lipoproteins (HDL), and HDL‐associated proteins apolipoprotein A1 (apoA1) and serum amyloid A (SAA) on markers of viability, cholesterol flux, and differentiation in K562 cells—a bone marrow‐derived, stem‐like erythroleukemia cell model of chronic myelogenous leukemia (CML). We further evaluated whether lipoprotein‐mediated effects were altered by concomitant LXR activation. We observed that LDL promoted higher K562 cell viability in a dose‐ and time‐dependent manner and increased cellular cholesterol concentrations, while LXR activation by the agonist TO901317 ablated these effects. LXR activation in the presence of HDL, apoA1 and SAA‐rich HDL suppressed K562 cell viability, while robustly inducing mRNA expression of ATP‐binding cassette transporter A1 (ABCA1). HDL and its associated proteins additionally suppressed mRNA expression of anti‐apoptotic B‐cell lymphoma‐extra large (BCL‐xL), and the erythroid lineage marker 5′‐aminolevulinate synthase 2 (ALAS2), while SAA‐rich HDL induced mRNA expression of the megakaryocytic lineage marker integrin subunit alpha 2b (ITGA2B). Together, these findings suggest that lipoproteins and LXR may impact the viability and characteristics of CML cells.