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Dispositional optimism, a personality trait predisposing individuals to positive expectations, has been suggested to promote better health. However, little is known about the biological mechanism of the salubrious health effects of optimism. We hypothesized that by diminishing a sense of threat to the self, optimism will be associated with a healthier profile of gene expression in immune cells. Specifically, the “conserved transcriptional response to adversity” (CTRA) is activated by fight-or-flight stress responses and results in increased transcription of genes involved in inflammation and decreased transcription of genes involved in antiviral defense. In a sample of 114 male Japanese workers, we found that optimism was inversely linked to CTRA after controlling for demographic variables, health-risk factors, and indices of well-being. These results are consistent with the hypothesis that reduced activity of threat-related gene expression programs may contribute to the health effects associated with optimism.