CONTEXT: Few studies have examined whether the inflammatory markers IL-6 and C-reactive protein (CRP) are associated with exceptional longevity. OBJECTIVE: Our objective was to determine the association of serum CRP and IL-6 with adult lifespan. DESIGN, SETTING, AND PARTICIPANTS: This was a prospective, population-based study of 610 men and 743 postmenopausal women, mean age 73 yr, who had serum IL-6 and CRP measurements at baseline (1984-1987) and who were followed for mortality for up to 23 yr (through 2008). Participants must have been old enough at baseline (57 yr) to have the potential to achieve age 80 during follow-up. MAIN OUTCOME MEASURES: Relative survival time and age at death (lifespan) were assessed. RESULTS: During follow-up, overall mortality was 69%. After adjustment for cardiovascular disease risk factors, in men, each sd increase in IL-6 was associated with a 15% decrease in survival time and 0.94-yr shorter lifespan (P < 0.001); corresponding values for CRP were a 12% decrease in survival time and a 1.00-yr reduction in lifespan (P < 0.001). Among women not using estrogen therapy (n = 532), survival time decreased 7% per sd higher IL-6 and lifespan was 1.35 yr shorter (P < 0.001). IL-6 was not related to lifespan among women using estrogen. CRP levels were not significantly associated with survival time or lifespan in women regardless of estrogen status. CONCLUSIONS: Higher levels of inflammatory markers predicted reduced survival time and shorter lifespan among older men, whereas only IL-6 was associated with longevity in postmenopausal women and only among those not using estrogen.