["The Journal of Physiology, Volume 604, Issue 13, Page 5512-5534, 1 July 2026. ", "\nAbstract figure legend We present a shape modelling‐based morphological analysis of sex differences in cardiac anatomy. We conduct our analysis on 456 healthy subjects from the UK Biobank (227M/229F) to uncover sex‐based differences in healthy cardiac morphology. Our analysis shows that sex differences in cardiac anatomy are not limited to average shape but span the entire morphological distribution. In addition, sex consistently accounts for at least 25% of the variability, even after accounting for age, systolic blood pressure and body size. Finally, no confounder correction scheme fully eliminates geometric differences between male and female hearts. Moving forward, accounting for these intrinsic differences in clinical biomarkers and imaging‐based diagnostic thresholds will be essential to reduce sex‐related disparities in cardiovascular care.\n\n\n\n\n\n\n\n\n\nAbstract\nSex‐based differences in cardiovascular disease are well documented, yet the precise nature and extent of these discrepancies in cardiac anatomy remain incompletely understood. Traditional scaling models often fail to capture the interplay of age, blood pressure and body size, prompting a more nuanced investigation. Here we use statistical shape modelling in a healthy subset (n = 456) of the UK Biobank to explore sex‐specific variations in biventricular anatomy. We reconstruct 3D meshes and perform multivariate analyses of shape coefficients, controlling for age, blood pressure and various body size metrics. Our findings reveal that sex alone explains at least 25% of morphological variability, with strong discrimination between men and women (AUC = 0.96–0.71) persisting even after correction for confounders. Notably, the most discriminative modes highlight pronounced differences in cardiac chamber volumes, the anterior–posterior width of the right ventricle and the relative positioning of the cardiac chambers. These results underscore that sex has a fundamental influence on cardiac morphology, which may have important clinical implications for differing cardiac structural assessments in men and women. Future work should investigate how these anatomical differences manifest in various cardiovascular conditions, ultimately paving the way for more precise risk stratification and personalised therapeutic strategies for both men and women.\n\n\n\n\n\n\n\n\n\nKey points\n\nMen's and women's hearts differ significantly in overall shape and size, but an in‐depth quantification of these sex differences in healthy cardiac anatomy is lacking.\nWe used a three‐dimensional statistical shape modelling approach that goes beyond standard clinical measurements to capture subtle anatomical features.\nOur findings show that sex alone accounts for at least 25% of the natural variation in heart structure, even after correcting for age, blood pressure and various body size metric confounders.\nFemale hearts consistently present smaller chambers and different inter‐chamber positioning compared with male hearts.\nOur findings highlight the importance of sex‐specific anatomical insights for better diagnosis, treatment and research on heart disease.\n\n\n"]