Glycation of apolipoprotein A-I (apoA-I) compromises its cardiovascular protection, yet its pathogenic landscape remains poorly defined. Using unbiased glycation proteomics, we profiled apoA-I glycation in HDL from 1,154 patients with type 2 diabetes mellitus with or without coronary atherosclerosis (CAS). CAS-associated glycation types, frequencies, and key sites enabled construction of an apoA-I glycation index. An engineered anti-glycation apoA-I mutant restored HDL reverse cholesterol transport and inhibited atherogenesis by preventing TR4-mediated suppression of macrophage cholesterol efflux.