Rationale: Hypertriglyceridemia and low HDL-C (high-density lipoprotein cholesterol), both of which are regulated by LpL (lipoprotein lipase) activity, associate with increased cardiovascular disease. Genetic regulators of LpL actions track with cardiovascular disease risk in humans. Whether this is due to changes in HDL-C or function or circulating triglyceride levels is unresolved. Objective: We created hypertriglyceridemia and HDL-C reduction in atherosclerotic mice to allow the assessment of how hypertriglyceridemia and reduced HDL-C affect regression of atherosclerosis and the phenotype of plaque macrophages. Methods and Results: Atherosclerosis regression was studied in control LpL floxed ( Lpl ^fl/fl ) mice and tamoxifen-inducible whole-body LpL knockout ( iLpl ^−/− ) mice with hypertriglyceridemia (≈500 mg/dL) and reduced HDL-C (≈50% reduction). Atherosclerosis regression was studied using 2 models in which advanced plaques resulting from hypercholesterolemia are exposed to normal LDL-C (low-density lipoprotein cholesterol) levels using aortic transplantation or treatments with oligonucleotides. In a subset of mice, we expressed hCETP (human cholesterol ester transfer protein) to humanize the relationship between apoB-lipoproteins and HDL. HDL particle number, cholesterol efflux capacity, and HDL proteome were measured in hypertriglyceridemia mice and humans. Surprisingly, hypertriglyceridemia and reduced HDL-C levels due to loss of LpL did not affect atherosclerosis lesion size or macrophage content (CD68+cells) in either model. Expression of hCETP and further reduction of HDL-C did not alter lesions. Sera from iLpl ^−/− mice had a decrease in total cholesterol efflux capacity, but not ABCA1 (ATP-binding cassette transporter A1)-mediated cholesterol efflux capacity. Hypertriglyceridemic humans, including those with LpL deficiency, had greater ABCA1-mediated cholesterol efflux capacity and total cholesterol efflux capacity per HDL particle number. Conclusions: Atherosclerosis regression in mice is driven by LDL-C reduction and is not affected by hypertriglyceridemia and plasma HDL-C levels.