Elevated triglycerides and non-HDL-cholesterol (C) are risk factors for atherosclerotic cardiovascular disease (ASCVD). AROANG3 is a RNA interference therapy targeting hepatocyte production of angiopoietin-like protein 3 (ANGPTL3), a regulator of lipoprotein metabolism. This Phase 1 trial (NCT03747224) investigated single and repeat doses of AROANG3 in healthy volunteers and repeat doses in subjects with hepatic steatosis. AROANG3 was well tolerated without adverse changes in liver fat in steatotic subjects. In healthy volunteers, ARO-ANG3 produced reductions in ANGPTL3 (mean − 45% to -78%) 12 weeks post-dose. Concurrent reductions in triglycerides (median 34% to 54%) and nonHDL-C (mean 18% to 29%) were observed with the 3 highest doses. Reduced LDL-C was seen with repeat dosing. The data support ANGPTL3 as a potential therapeutic target for treatment of ASCVD.