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Inflammation may play a role in increased risk of heart failure (HF) that is associated with obesity, metabolic syndrome (MS), and diabetes. This study investigated associations between inflammatory markers, MS, and incident HF in a population with a high prevalence of diabetes, obesity, and MS. The cohort consisted of 3098 American Indians without prevalent cardiovascular disease who had C-reactive protein (CRP) and fibrinogen measured at the Strong Heart Study phase II examination. Independent associations between inflammatory markers, MS, and HF were analyzed by Cox hazard models. During a mean follow-up of 11 years, 218 participants developed HF. After the adjustment for cardiovascular risk factors, fibrinogen, (hazard ratio [HR], 1.36; 95% confidence interval [CI], 1.15-1.59) but not CRP (HR, 1.25; 95% CI, 0.97-1.32) remained a significant HF predictor. In individuals without diabetes, concomitant presence of MS and elevated CRP or fibrinogen increased HF risk (for MS and CRP: HR, 2.02; 95% CI, 0.95-4.31; for CRP and fibrinogen: HR, 1.75; 95% CI, 0.83-3.72). In a population with a high prevalence of obesity, MS, and diabetes, elevated CRP and fibrinogen increased HF risk. These associations are attenuated by the adjustments for conventional risk factors suggesting that inflammation acts in concert with metabolic and clinical risk factors in increasing HF risk. [ABSTRACT FROM AUTHOR]