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Recent research suggests that optimism may reduce the risk of incident cardiovascular disease, but the mechanisms have not been determined. This study examines the association of optimism with change in inflammation and endothelial function over time in men.Longitudinal data were obtained from the Normative Aging Study excluding men with preexisting coronary heart disease or active infection at the time optimism was assessed (n = 340; mean [standard deviation] age = 70.9 [6.7] years). The Life Orientation Test was used to measure optimism, and serum markers were used to measure inflammation and endothelial dysfunction and were obtained repeatedly during the course of the study (1999-2008). These markers included high-sensitivity C-reactive protein, interleukin 6, soluble intercellular adhesion molecule 1, soluble vascular cell adhesion molecule 1, and soluble tumor necrosis factor receptor II. Within this sample, 243 men (71%) had two or more repeated measures of each outcome, resulting in a total of 746 observations for analysis. Linear mixed-effects models with a random subject intercept were used to estimate associations.Higher overall optimism scores were associated with lower levels of interleukin 6 and soluble intercellular adhesion molecule 1 pooled across multiple time points in multivariable models but were not associated with rate of change in these markers over time. Analyses considering separate effects of optimism and pessimism subscales with each outcome indicated stronger effects of a pessimistic orientation versus an optimistic orientation.Higher overall optimism scores were associated with lower levels of inflammation and endothelial dysfunction in older men free of coronary heart disease.