OBJECTIVES: To investigate the effect of coagulation and inflammatory pathway activation on future cognitive decline in older persons. DESIGN: Prospective cohort study. SETTING: Rural and urban communities in North Carolina. PARTICIPANTS: Community-dwelling older people enrolled in the Duke Established Populations for Epidemiologic Studies of the Elderly in 1986. MEASUREMENTS: In 1992, blood was drawn for assay of D-dimer (1,723 subjects), Interleukin-6 (1,726 subjects), and other cytokines (1,551 subjects). Cognitive and functional assessments were performed in 1986, 1989, 1992, and 1996. Cognition was measured using the Short Portable Mental Status Questionnaire. RESULTS: Cognitive decline over a 4-year period was significantly correlated (P<.001) with D-dimer, age, race, and physical performance status as measured using the Rosow-Breslau and Nagi instruments. After controlling for demographics, functional status, and comorbidities, D-dimer remained predictive of cognitive decline. Proinflammatory cytokines were not associated with current cognitive status in cross-sectional analyses or with incident cognitive decline in prospective analyses. CONCLUSION: In a large sample of community-dwelling elders, higher levels of D-dimer were predictive of cognitive decline over a 4-year period. No clinically significant associations were found between age-related peripheral cytokine dysregulation and cognition.