Abstract Body (Do not enter title and authors here): Premenopausal females show less adverse remodeling following a myocardial infarction (MI) compared with age-matched males. Despite this, little is known regarding the changes that contribute to the increased resilience of the female heart to pathological stress. Therefore, this study aimed to understand the extent to which biological sex influences structural and functional remodeling of the heart following MI. We subjected 20-week-old male and female C57BL/6J mice to either sham or non-reperfused MI surgery and measured changes in cardiac structure and function up to 4-weeks post-surgery. Data are mean±SD. Notably, 2,3,5-Triphenyltetrazolium chloride staining assessed one day after MI revealed that both sexes had comparable infarct sizes (MvF: 43±6% v 41±8%, n=6/grp). In a separate cohort, echocardiographic analysis at 4 weeks post-MI revealed lower ejection fraction (MvF EF: 14.9±3.3 v 40.9±18.4%; p<0.02, n=6–11/grp), increased heart size (MvF LV mass: 236±68 v 138±54 mg; p<0.01, n=6–11/grp), and increased chamber dimensions (MvF LVEDV: 259±49 v 105±38 µl; p<0.0001, n=6–11/grp) in post-MI males versus females. Although ischemic zone fibrosis was comparable between male and female MI hearts (MvF 54.4±11.1 v 57.2±14.1 %), scar thickness was increased in male versus female hearts (582±227 v 322±79 μm; p<0.05) and polarized light microscopy of picrosirius red-stained MI scars revealed increased alignment of collagen fibers in male versus female hearts (0.75±0.07 v 0.61±0.11; p<0.05). We performed bulk cardiac metabolomics in hearts 4 weeks post-surgery to further examine these sex-dependent differences. We observed significant increases in metabolites involved both in and upstream of collagen catabolism, including trans-4-hydroxyproline and 5-(galactosylhydroxyl)-L-lysine, UDP-glucuronate, in male versus female hearts. Spatial transcriptomics analysis of the infarct zone of MI hearts revealed significant increases in the expression of collagen crosslinking and hydroxylation transcripts (e.g., Lox, Loxl2, Loxl3, Plod1, Plod2, Plod3), ECM regulatory genes (e.g., Timp1, Timp2, Mmp2, Mmp12, Adam8, Comp, Sfrp2), matricellular proteins (e.g., Sparc, Cyr61), and collagen isoforms (e.g., Col1a1, Col5a1, Col8a2, Col12a1, Col14a1) in female hearts. Together, these data suggest sex-dependent differences in collagen processing and crosslinking that likely afford a more compliant matrix and contribute to increased female cardiovascular resilience.