The I148M (rs738409-G) variant in PNPLA3 increases liver fat content but may be protective against cardiovascular disease. Insulin resistance (IR) amplifies the effect of PNPLA3-I148M on liver fat.To study whether PNPLA3-I148M confers an antihyperlipidemic effect in insulin-resistant patients.Cross-sectional study comparing the impact of PNPLA3-I148M on plasma lipids and lipoproteins in two cohorts, both divided into groups based on rs738409-G allele carrier status and median HOMA-IR.Tertiary referral center.298 obese patients who underwent a liver biopsy during bariatric surgery (Bariatric cohort; age 49±9 years, BMI 43.2±6.8 kg/m 2), and 345 less obese volunteers in whom liver fat was measured by proton magnetic resonance spectroscopy (Non-bariatric cohort; age 45±14 years, BMI 29.7±5.7 kg/m 2).Nuclear magnetic resonance profiling of plasma lipids, lipoprotein particle subclasses and their composition.In both cohorts, individuals carrying the PNPLA3-I148M variant had significantly higher liver fat content than non-carriers. In insulin-resistant and homozygous carriers, PNPLA3-I148M exerted a distinct antihyperlipidemic effect with decreased very-low-density lipoprotein (VLDL) and low-density lipoprotein particles (LDL) and their constituents, and increased high-density lipoprotein particles and their constituents, as compared to non-carriers. VLDL particles were smaller and LDL particles larger in PNPLA3-I148M carriers. These changes were geometrically opposite to those due to IR. PNPLA3-I148M did not have a measurable effect in patients with lower IR, and its effect was smaller albeit still significant in the less obese compared to the obese cohort.PNPLA3-I148M confers an antiatherogenic plasma lipid profile particularly in insulin-resistant individuals.