Very low-density lipoproteins (VLDL) are precursors of low-density lipoproteins (LDL, or "bad cholesterol"). Factors affecting structural integrity of VLDL are important for their metabolism. To assess the role of electrostatic interactions in VLDL stability, we determined how solvent ionic conditions affect the heat-induced VLDL remodeling. This remodeling involves VLDL fusion, rupture, and fission of apolipoprotein E-containing high-density lipoprotein-(HDL-) like particles similar to those formed during VLDL-to-LDL maturation. Circular dichroism and turbidity show that increasing sodium salt concentration in millimolar range reduces VLDL stability and its enthalpic component. Consequently, favorable electrostatic interactions stabilize VLDL. Reduction in pH from 7.4 to 6.0 reduces VLDL stability, with further destabilization detected at pH < 6, which probably results from titration of the N-terminal α-amino groups and free fatty acids. This destabilization is expected to facilitate endosomal degradation of VLDL, promote their coalescence into lipid droplets in atherosclerotic plaques, and affect their potential use as drug carriers.