Depressed baroreflex sensitivity (BRS) is associated with an increased risk of mortality in patients with a known cardiac disease. The prognostic significance of BRS in subjects without history of major cardiovascular (CV) events is unknown. The present study tested the hypothesis that impaired BRS predicts the CV mortality in a population-based sample of middle-aged subjects. The present study is a part of the Oulu Project Elucidating Risk of Atherosclerosis study, where middle-aged hypertensive and age- and gender-matched control subjects were randomly selected. Along with clinical and laboratory assessments, BRS was measured from the blood pressure overshoot of Valsalva maneuver in 559 subjects (age 51 ± 6 years; 300 men). The causes of death (n = 72) were registered during a follow-up of up to 19 years. CV death (n = 23) was defined as the primary end point. CV death was predicted by smoking status, alcohol consumption, high-sensitivity C-reactive protein, use of diuretics, waist circumference, and fasting glucose. Among all measured risk factors, impaired Valsalva BRS (<3 ms/mm Hg) was the most potent predictor of CV death (hazard ratio 9.1, 95% confidence interval 3.8 to 21.7, p <0.001) and remained so after adjustments for the other significant predictors (hazard ratio 5.3, 95% confidence interval 2.1 to 13.3, p <0.001). In conclusion, impaired Valsalva BRS is a potent and independent predictor of CV death in a population-based sample of middle-aged subjects without history of major CV complications and may have important clinical implications in early risk stratification.