Background Previous studies observed the surprising finding that saturated fat was inversely associated with atherosclerosis progression in postmenopausal women, whereas polyunsaturated fat (PUFA) and carbohydrates were positively associated. Whether certain genes modify the association of diet with atherosclerotic progression is unknown. Methods Using Haplotype-tagging single nucleotide polymorphisms, we evaluated gene-diet interactions with 3 preselected genes involved in fatty acid and carbohydrate metabolism: sterol regulatory element binding protein-1 (SREBP1), insulin-induced gene-1 (INSIG1), and SREBP cleavage-activating protein (SCAP). Diet was assessed at baseline. Quantitative coronary angiography was performed at baseline and after a mean of follow-up of 3.09 years in 2,227 coronary segments in 234 postmenopausal women. Results Global effects of each gene and gene-diet interactions for different fats, total fat, and carbohydrate were evaluated. Global tests revealed no main effects between SCAP, INSIG1, and SREBP1 haplotypes and progression of atherosclerosis (P = .87, P = .58, and P = .44). After correction for 5 nutrients evaluated (Bonferroni-corrected 2-tailed α = .01), no significant gene-nutrient interactions were seen, except for a borderline global interaction between SREBP1 and PUFA intake (P interaction = .013). This interaction was specific to the G-C haplotype (frequency 35%) and was driven by n-6 rather than n-3 PUFA (P for interaction < .0001). The interaction was robust to estimated isocaloric replacement of PUFA with any other nutrient. Per each 5% energy from n-6 PUFA, a 0.21-mm greater decline in mean minimal coronary artery diameter was seen among women per each copy of the second most frequent haplotype of SREBP1. Conclusions We observed an interaction between SREBP1 and PUFA consumption that might explain the positive association of PUFA with atherosclerosis progression in this cohort.