Uteroplacental insufficiency (UPI) causes intrauterine growth restriction, which has been widely accepted as a risk factor for hypercholesterolemia and hepatic cholesterol accumulation in adulthood. Free cholesterol accumulation in liver determines susceptibility to oxidative stress and promotes hepatotoxicity. We aimed to gain mechanistic insights into hepatic cholesterol accumulation in UPI-induced low birth weight (LBW) offspring in adulthood. Uterine artery ablation-induced LBW and normal birth weight (NBW) male and female guinea pig offspring were fed a regular diet from weaning until tissue collection at postnatalday 150. Hepatic cholesterol, superoxide dismutase (SOD) and catalase (CAT) activitieswere spectrophotometrically determined. Differentially expressed genes (DEGs) in livers were identified by transcriptomics using the GeneChip™ Guinea Pig Gene 1.1 ST Array Plate and TAC software. Complementary immunoblottings were performed. Hepatic cholesterol esters, free and total cholesterol were only increased in male LBW versusNBW (p<0.05). Transcriptomic analysis of LBW versusNBW livers revealed 51 and 31 DEGs in males and females, respectively (-2<fold change>2; p<0.05). The overrepresented pathways associated with DEGs in LBW males were “cholesterol metabolism” and “PPAR signalling” (p<0.05). The mRNAs, Apoa1and Angplt4, both related to reverse cholesterol transport were upregulated in male LBW livers. Proteinabundance of Microsomal triglyceride transfer protein and cytochrome P450 7A1, involved in hepatic cholesterol elimination, and the antioxidant enzyme CAT were decreased in LBW male livers (p<0.05). These findings suggest that UPI potentially programs hepatic cholesterol accumulation in a sex-specific manner via impaired hepatic cholesterol elimination. This potentially sets the stage for later life cholesterol-induced hepatotoxicity in LBW male offspring.