Inflammation is a ubiquitous underlying mechanism of the links between diet and cognitive functioning. No study has yet evaluated the overall inflammatory potential of the diet, using the dietary inflammatory index (DII), in relation to cognitive functioning. In a French cohort of middle-aged adults, we evaluated the association between the DII, assessed in midlife, and cognitive performance evaluated 13 years later. The DII is a literature-derived dietary index developed to determine the inflammatory potential of diet. The DII was estimated at baseline (1994-1996) among 3080 subjects of the SU.VI.MAX (supplementation with antioxidant vitamins and minerals) cohort. Cognitive performance was assessed in 2007-2009 via a battery of standardized neuropsychological tests. Principal component analysis was performed to extract a summary score of cognitive performance. Multivariable-adjusted linear regression analyses were performed to provide regression coefficients and 95 % confidence intervals (95 % CI). In a multivariate model, a strong inverse association was observed between a higher DII (reflecting a more inflammatory diet) and overall cognitive functioning (mean difference Q4 vs. Q1 = -1.76; 95 % CI = -2.81, -0.72, P for trend =0.002). With regard to specific cognitive domains, similar associations were observed with scores reflecting verbal memory, but not executive functioning. This study suggests that a pro-inflammatory diet at midlife might be associated with subsequent lower cognitive functioning. A diet exhibiting anti-inflammatory properties may help to maintain cognitive health during aging. Clinicaltrials.gov (number NCT00272428).