Orthostatic hypotension (OH) is associated with increased total mortality but contribution of specific death causes has not been thoroughly explored. In this prospective study, authors followed up 32,068 individuals without baseline history of cancer or cardiovascular disease (69% men; mean age, 46 years; range, 26-61 years) over a period of 24 years. Hazard ratios (HRs) for total and cause-specific mortality associated with presence of OH and by quartiles of postural systolic blood pressure response (∆SBP) were assessed using multivariate adjusted Cox regression model. A total of 7,145 deaths (22.3%, 9.4 deaths/1,000 person-years) occurred during follow-up. Those with OH (n = 1,943) had higher risk of death due to injury (HR, 1.88; 1.37-2.57) and neurological disease (HR, 2.21; 1.39-3.51). Analogically, risk of death caused by injury and neurological disease increased across the quartiles of ∆SBP from hyper- (Q1(SBP), +8.5 ± 4.7 mmHg) to hypotensive response (Q4(SBP), -13.7 ± 5.7 mmHg; HR, 1.32; 1.00-1.72, and 1.84; 1.20-2.82, respectively) as did also risk of death due to respiratory disease (Q4(SBP) vs. Q1(SBP): HR, 1.53; 1.14-2.04). In contrast, risk curve for cerebrovascular death was U-shaped with nadir in the mildly hypotensive 3rd quartile of ∆SBP (-5.0 ± 0.1 mmHg, Q3(SBP) vs. Q1(SBP): HR, 0.75; 0.54-1.03; P for linear trend = 0.021). Additionally, cardiovascular mortality was increased among 5,805 rescreened participants (mean age, 53 years; 9.8% OH positive: HR, 1.54; 1.24-1.89, and Q4(SBP) vs. Q1(SBP): 1.27; 1.02-1.57, respectively). In summary, increased mortality predicted by blood pressure fall on standing is associated with injuries, neurodegenerative, and respiratory diseases, as well as with cardiovascular disease in older adults. Moreover, both increase and pronounced decrease of SBP during early orthostasis indicate higher risk of cerebrovascular death.