Positive psychological attributes have been associated with better health outcomes, although the mechanisms remain poorly understood. This study examined associations between life satisfaction and inflammatory biomarkers. Participants were 369 men and 428 women (aged 52.1 ± 16.8 years) recruited from the general population. Participants were required to rate their life satisfaction on a scale ranging from 0 (extremely dissatisfied) to 10 (extremely satisfied). Blood was collected for the measurement of C-reactive protein (CRP) and fibrinogen. In comparison with participants that were dissatisfied with life (5.8% of the sample), those that reported high life satisfaction demonstrated a lower CRP concentration (beta coefficient = −.24, 95% CI, −.47, −.02) and lower fibrinogen (β = −.24, 95% CI, −.45, −.04) after adjusting for age, sex, education, smoking, body mass index, and depressive symptoms. Life dissatisfaction was also associated with smoking, lower education, and depressive symptoms. In summary, lower levels of circulating inflammatory markers might be an important psychobiological process through which positive psychological attributes protect against disease risk.