Background: Compared to males, females have smaller hearts, with decreased left ventricular (LV) internal dimensions, wall thicknesses and volumes, and increased ejection fractions (EF) (Buonanno et al. 1982; Chung et al. 2006; Sandstede et al. 2000). It has additionally been demonstrated that resting LV strains are increased in females (Lawton et al. 2011). As LV mechanics are preload-dependent, it is feasible that the known structural and functional differences in the female heart will result in altered LV mechanics (twist, rotation and strain) when challenged with an acute change in preload. This study aimed to determine sex-differences in LV mechanics during incremental reductions to preload using lower body negative pressure (LBNP). Methods: Healthy human subjects, 20 males (M; age = 24 ± 6.2 yr) and 20 females (F; age = 23 ± 3.1 yr) were assessed at baseline, and during incremental steps of LBNP (-20, -40 and -60 mmHg) to reduce preload. Two-dimensional echocardiographic images were acquired (Vivid-q, GE Healthcare) for the assessment of LV rotation and twist parameters using speckle-tracking analysis software (EchoPac, GE Healthcare). LV torsion was calculated as peak twist angle divided by LV end-diastolic length. Statistical significance was assessed using a two-way repeated measures ANOVA, with a Fisher’s Least Significant Difference post-hoc. Values are reported as means ± SD. Results: Both LV end-diastolic and end-systolic volumes were reduced with increasing LBNP (p<0.001), but remained higher in males at all levels of LBNP (p<0.001). LV EF and stroke volume (SV) also decreased during LBNP (p<0.001), with SV being consistently smaller in females compared to males (p<0.001). Sex-differences were not detected at baseline in basal rotation (M: -3.2 ± 2.7°; F: -4.1 ± 2.4°), apical rotation (M: 10.6 ± 3.7°; F: 12.4 ±4 .5°) or twist (M: 13.6 ± 4.6°; F: 16.1 ± 5.9°). Apical rotation and LV twist increased in both groups (p<0.001) with LBNP. At -60 mmHg, females had greater apical rotation (M: 13.1 ± 5.9°; F: 18.0 ± 6.9°; p<0.01) and twist (M: 15.8 ± 4.8°; F: 21.4 ± 6.7°; p<0.01) than males. Adjusting for LV length, females also had greater LV torsion than males at -40 (M: 1.5 ± 0.5°×cm-1; F: 2.3 ± 0.7°×cm-1; p<0.05) and -60 mmHg (M: 1.9 ± 0.7°×cm-1; F: 2.8 ± 0.9°×cm-1; p<0.01). Conclusion: Females appear to utilize greater LV twist during acute reductions to preload. As LV torsion was also greater in females, the sex-differences appear to be unrelated to differences in LV longitudinal dimension. Overall, these findings suggest that LV mechanics may be more preload-dependent in females than males. More specifically, greater myocardial deformation in females compensates in attempt to maintain stroke volume when preload is reduced.