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Optimism is associated with better health, and inflammatory activity has been proposed as a potential biological pathway. However, the evidence implicating inflammation has been adduced by cross-sectional studies, and the directionality of the optimism-inflammation relationship has remained unclear. The present longitudinal analyses therefore tested if optimism predicts inflammatory activity or whether inflammation predicts optimism. Participants (N = 6.890; 59% Female; Mean age 57 years; Range 18–90) were recruited as part of a nation-wide study on cardiovascular risk factors in primary care (DETECT study). Data were collected in 2003, 2004, and 2007. Health and lifestyle data were provided by clinical examination and patient self-report. Questionnaires assessed dispositional optimism (LOT-R) and depression (DSQ). Plasma C-Reactive Protein (CRP) was used as a marker of inflammation. Cross-sectional analyses confirmed an inverse relation between optimism and inflammation, adjusting for age, gender, SES, lifestyle (smoking, alcohol, BMI), health status, and depression (p <.01). Longitudinal analyses showed that optimism also predicted lower inflammation at +1 year (applying the same adjustments, as well as adjusting for inflammation at baseline; p <.01) and at +4 years, although the latter association did not survive full adjustment for health behaviors. Conversely, inflammation at baseline did not predict optimism measured 1 or 4 years later (p >.40). These longitudinal data revealed that optimism is a predictor of inflammation, but provided no support for a reverse association. [ABSTRACT FROM AUTHOR]