Efficient delivery of specific cargos in vivo poses a major challenge to the secretory pathway, which shuttles products encoded by ∼30% of the genome. Newly synthesized protein and lipid cargos embark on the secretory pathway via COPII-coated vesicles, assembled by the GTPase SAR1 on the endoplasmic reticulum (ER), but how lipid-carrying lipoproteins are distinguished from the general protein cargos in the ER and selectively secreted has not been clear. Here, we show that this process is quantitatively governed by the GTPase SAR1B and SURF4, a high-efficiency cargo receptor. While both genes are implicated in lipid regulation in humans, hepatic inactivation of either mouse Sar1b or Surf4 selectively depletes plasma lipids to near-zero and protects the mice from atherosclerosis. These findings show that the pairing between SURF4 and SAR1B synergistically operates a specialized, dosage-sensitive transport program for circulating lipids, while further suggesting a potential translation to treat atherosclerosis and related cardio-metabolic diseases. Display omitted •Lipoprotein transport is segregated from general secretion upon ER exiting•The cargo receptor SURF4 selectively transports lipoproteins from the ER•Lipid-associated non-coding SNP in humans regulates SURF4 expression•Dose-dependent SURF4 loss in mice prevents hyperlipidemia and atherosclerosis Xiao-Wei Chen and colleagues report that synergistic pairing between the cargo receptor SURF4 and the GTPase SAR1B defines a selective transport program for circulating lipoproteins from the ER. They also show that genetic depletion of Surf4 in mice strongly protects from atherosclerosis development.