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To study the prospective relationship of blood pressure response during orthostatic challenge with incidence of heart failure (HF).In a Swedish prospective cohort study (the Malmö Preventive Project), we followed up 32 669 individuals (68.2% men; mean age, 46 years) over a period of 24 years. Incidence of first hospitalization due to new-onset HF was related to early (60–120 s) postural changes in systolic and diastolic blood pressure (ΔSBP and ▵DBP), and mean arterial pressure (ΔMAP), using Cox proportional hazards models. Hazard ratio of incident HF increased across descending quartiles of ΔSBP from the first (and reference) quartile (+8.5 ± 4.9 mmHg), through the second (neutral response), to the third and fourth quartiles (−5.0 ± 0.1 and −13.7 ± 6.1 mmHg, respectively; P for linear trend=0.009). A pronounced hypotensive SBP response (fourth quartile) conferred the highest risk of new-onset HF [hazard ratio (HR), 1.31; 95% confidence interval (CI), 1.11–1.53]. A similar pattern was observed with regard to ΔMAP, where the first (and reference) quartile with a marked positive MAP response (+7.7 ± 3.1 mmHg) had the lowest, and the fourth quartile with a hypotensive MAP response (−5.2 ± 3.4 mmHg) had the highest HF risk (HR for fourth vs. first quartile: 1.37; 95% CI, 1.17–1.62). In a continuous model, the risk of incident HF conferred by negative ΔSBP matched that of resting SBP (HR per 10 mmHg difference: 1.17; 95% CI, 1.11–1.23, and 1.17, 1.14–1.20, respectively), whereas MAP drop was the strongest individual predictor of HF development (HR 1.26, 95% CI, 1.21–1.31).Early increase of blood pressure in response to orthostatic challenge signals reduced the risk of HF development.