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To examine prospectively the association of psychological distress with the development of the metabolic syndrome (MetS) and the potential influence of demographic characteristics, health behaviors, and inflammation in this association.A total of 466 (n = 185 males; 281 females) subjects, aged 36 to 56 years, and free of MetS at baseline, participated in a population-based study from 1997 to 1998 and again from 2004 to 2005. Mean observation time was 6.4 years. Various clinical, biochemical, and behavioral factors were measured at baseline, including assessment of psychological distress using the 12-item General Health Questionnaire. The development of MetS was measured at follow-up based on National Cholesterol Education Program criteria.Subjects with high psychological distress at baseline (General Health Questionnaire scores, 4–12) were more than twice as likely to develop MetS than those with low psychological distress (odds ratio, 2.18; 95% confidence interval, 1.30–3.64). Adjustments for 1) age, gender, and sociodemographic variables; 2) health behaviors (smoking, alcohol use, and leisure time physical activity); and 3) C-reactive protein in the analysis diminished the odds of developing MetS in the distressed group (odds ratio, 1.87; 95% confidence interval, 1.83 and 1.81, respectively); however, the association remained statistically significant (p = .025–.038).Psychological distress at baseline increases the risk of developing MetS during follow-up. This association remained robust after adjusting for age, gender, sociodemographic variables, baseline health behaviors, and C-reactive protein. These prospective findings are evidence of a significant association between psychological distress and the development of MetS.MetS = metabolic syndrome; GHQ-12 = 12-item General Health Questionnaire; SD = standard deviation; OR = odds ratio; CI = confidence interval; CRP = C-reactive protein; hsCRP = high-sensitivity C-reactive protein; HDL = high-density lipoprotein; NCEP-ATP III = National Cholesterol Education Program-Adult Treatment Panel III; BDI = Beck Depression Inventory.