We explored global myocardial work index (GWI), a novel measure of myocardial function that integrates left ventricular (LV) hemodynamic load, in relation to sex and increased body mass index (BMI). We used data from 467 individuals (61% women, average age 47 ± 9 years and BMI 31.2 kg/m2) without known cardiac disease. Central arterial function was analysed by applanation tonometry. GWI was calculated from global longitudinal strain (GLS) and post-echocardiography supine blood pressure (BP). Covariables of GWI were identified in linear regression analyses. Women had higher BMI, aortic augmentation pressure (12 ± 7 vs. 8 ± 6 mmHg), LV GLS (20.0 ± 2.8 vs. 18.8 ± 2.8%), and GWI (2126 ± 385 vs. 2047 ± 389 mmHg%) than men (all p < 0.05). In univariable analyses, higher GWI was associated with female sex, higher age, systolic BP, LV wall stress, LV ejection fraction, left atrial size, LV ejection time, and with lower waist circumference (all p < 0.05). In multivariable analysis, adjusting for these correlates, female sex remained independently associated with higher GWI (β = 0.13, p = 0.007). After additional adjustment for aortic augmentation pressure or central pulse pressure, this association became non-significant. In conclusion, the higher GWI in women compared to men was mainly explained by increased LV workload due to higher aortic augmentation pressure in women.