OBJECTIVES: To assess whether C-reactive protein (CRP) and interleukin-6 (IL-6) are associated with low cognitive performance and decline in middle-aged adults. DESIGN/SETTING: The Whitehall II study; an ongoing large-scale, prospective occupational cohort study of employees from 20 London-based white-collar Civil Service departments. PARTICIPANTS: Data from more than 3000 males and 1200 female employees. MEASURES: Inflammatory makers measured in 1991-1993 and five cognitive tests (short-term verbal memory, inductive reasoning (AH4-I), vocabulary (Mill Hill), and phonemic and semantic fluency) performed in 1997-1999 and 2002-2004. Performance in the lowest sex-specific quintile indicated low cognitive performance or decline. Covariates included sociodemographics, health behaviours and health conditions. RESULTS: In age-adjusted analyses both CRP and IL-6 were associated with all cognitive measures in 1997-1999, even though the association with memory was not consistent. After extensive adjustment raised CRP levels were only associated with poor cognitive performance on the AH4-I (OR=1.38; 95% CI: 1.05-1.82) and Mill Hill (OR=1.52; 95% CI: 1.14-2.03) and IL-6 on semantic fluency (OR=1.27; 95% CI: 1.14-2.03). Associations were more evident in men than in women. No clear relationship was observed for decline. CONCLUSIONS: Our results suggest that raised levels of inflammatory markers in midlife are moderately associated with lower cognitive status, but little with cognitive decline.