BACKGROUND: -Endothelial lipase is a phospholipase with activity against high density lipoprotein. Although a small number of mutations in LIPG have been described, the role of LIPG in protection against atherosclerosis is unclear. METHODS AND RESULTS: -We identified eight loss-of-function (LOF) mutations in LIPG in individuals with high HDL-C. Functional analysis confirmed that most rare mutations abolish lipase activity in vitro, indicating complete LOF (CLOF), while two more common mutations N396S and R476W reduce activity by ~50%, indicating partial LOF (PLOF), and implying ~50% and ~75% remaining EL function in heterozygous CLOF and PLOF mutation carriers respectively. CLOF mutation carriers had significantly higher plasma HDL-C levels compared to PLOF mutation carriers. Apo-B depleted serum from CLOF carriers showed significantly enhanced cholesterol efflux acceptor capacity, whereas only trends were observed in PLOF carriers. Carriers of LIPG mutations exhibited trends toward reduced CAD in four independent cohorts (meta-analysis OR=0.7, p=0.04). CONCLUSIONS: -Our data suggest that the impact of LIPG mutations is directly related to their effect on EL function, and support that antagonism of EL function improves cardioprotection.