Background Cardiovascular disease (CVD) is the leading cause of mortality worldwide in both men and women, which is due in part to high prevalence of hypertension. Recent evidence suggests supine, standing, and possibly change in supine to standing blood pressure (BP) may have greater utility to predict future mortality risk compared to the traditionally assessed resting seated BP. We hypothesized that supine, standing and change from supine to standing SBP would have predictive value of all-cause mortality for both men and women. Methods The Ball State Adult Fitness Longitudinal Lifestyle (BALL ST) cohort was used for this analysis. The population consisted of 2,116 apparently healthy men and women with no known disease where BP measurements were acquired in the standing and supine positions and the change in supine to standing was calculated. The mean age was 46.2±13.0 yr for men and 44.8±13.2 yr for women. Participants were followed for an average of 18.2±9.0 yr for all-cause mortality. Additionally, measurements of traditional risk factors were obtained. Hazard ratios (95% CIs) were generated for association between BP (supine, standing, change) and all-cause mortality by sex. Multiple Cox proportional hazard models were fit to the following data: 1) BP unadjusted, 2) BP adjusted for age and testing year, 3) BP further adjusted for risk factor (obesity, hypertension, dyslipidemia, diabetes, physical inactivity, and smoking status), 4) BP further adjusted for hypertensive medications. Results Two hundred and ten participants died during the follow-up period. Within the whole cohort, the univariate model indicated a positive association between all-cause mortality for supine SBP (HR: 1.030, 95% CI: 1.023-1.038, p<0.05) and standing SBP (HR: 1.023, 95% CI:1.016-1.031, p<0.05). Mortality was associated with the change in SBP (HR: 1.021, 95% CI: 1.007-1.036) in women only (p<0.05). Change in SBP was correlated with all-cause mortality after adjusting for risk factors only in women (HR: 1.025, 95% CI: 1.000-1.051; p≤0.05). Diastolic blood pressure (DBP) in the supine (HR: 1.030, 95% CI: 1.016-1.044), and standing (HR: 1.014, 95% CI: 1.001-1.028) positions in women, and change in DBP (HR: 1.013, 95% CI: 1.013-1.063) in men were correlated with all-cause mortality in the univariate model only (p<0.05, all). Conclusion These findings demonstrate the change from supine to standing SBP predicts risk for all-cause mortality in women, but not men after adjusting for risk factors. Assessing positional blood pressure may provide clinicians with additional diagnostic insight and predict all-cause mortality risk in women.