BACKGROUND: Peripheral arterial disease is associated with a high incidence of cardiovascular mortality. Peripheral arterial disease can be detected by using the ankle-brachial index (ABI). This study assessed the prognostic value of the postexercise ABI in addition to the resting ABI on long-term mortality in patients with suspected peripheral arterial disease. METHODS: In this prospective cohort study of 3209 patients (mean +/- SD age, 63 +/- 12 years; 71.1% male), resting and postexercise ABI values were measured and a reduction of postexercise ABI over baseline resting readings was calculated. The mean follow-up was 8 years (interquartile range, 4-11 years). RESULTS: During follow-up, 1321 patients (41.2%) died. After adjusting for clinical risk factors, lower resting ABI values (hazard ratio per 0.10 lower ABI, 1.08; 95% confidence interval [CI], 1.06-1.10), lower postexercise ABI values (hazard ratio per 0.10 lower ABI, 1.09; 95% CI, 1.08-1.11), and higher reductions of ABI values over baseline readings (hazard ratio per 10% lower ABI, 1.12; 95% CI, 1.09-1.14) were significantly associated with a higher incidence of mortality. In patients with a normal resting ABI (n = 789), a reduction of the postexercise ABI by 6% to 24%, 25% to 55%, and greater than 55% was associated with a 1.6-fold (95% CI, 1.2-2.2), 3.5-fold (95% CI, 2.4-5.0), and 4.8-fold (95% CI, 2.5-9.1) increased risk of mortality, respectively. CONCLUSIONS: Resting and postexercise ABI values are strong and independent predictors of mortality. A reduction of postexercise ABI over baseline readings can identify additional patients (who have normal ABI values at rest) at increased risk of subsequent mortality.