Context: Low adiponectin concentrations are associated with the presence of an adverse cardiovascular disease (CVD) risk profile. Objective: We studied the predictive value of adiponectin levels for all-cause and CVD mortality and CVD morbidity. Design, Setting, and Participants: This was a population-based cohort study in Hoorn, The Netherlands, which started in 1989 and included 2484 participants, aged 50-75 yr. Main Outcome Measures: Hazard ratios (HRs) with 95% confidence interval per SD change in log-adiponectin for all-cause and CVD mortality and CVD morbidity were calculated. Results: Adiponectin was determined for 1077 men and 1248 women. Higher adiponectin reduced the risk of nonfatal CVD in women [HR with 95% confidence interval 0.72 (0.61-0.90) in women and 0.92 (0.79-1.06) in men], but not the risk of all-cause or CVD mortality. In contrast, after adjustment for cardiovascular risk factors, higher adiponectin was a significant predictor of all-cause and CVD mortality [HR for CVD mortality 1.45 (1.10-1.92) in women and 1.30 (1.04-1.63) in men]. Higher adiponectin was associated with an increased risk of CVD mortality in people with prevalent CVD [HR 1.27 (0.98-1.63)] and with reduced risk in people without [HR 0.90 (0.73-1.11)]. After adjustment for cardiovascular risk factors, the HRs for CVD mortality were 1.60 (1.14-2.23) for patients with and 1.38 (1.06-1.80) for patients without prevalent CVD. Conclusions: High levels of adiponectin predict mortality, in particular in patients with prevalent CVD. We hypothesize that adiponectin protects against metabolic and vascular diseases, but in patients already afflicted with CVD, adiponectin is compensatory up-regulated and, therefore, indicates a high mortality risk. Copyright © 2008 by The Endocrine Society.