Background/Objectives:To clarify the association of serum docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) levels with cognitive decline over 10 years.Subjects/Methods:This study was part of the National Institute for Longevity Sciences - Longitudinal Study of Aging, and was conducted with 232 male and 198 female Japanese community-dwelling subjects aged 60–79 years in the second wave (2000–2002). Cognitive function was assessed with the Mini-Mental State Examination (MMSE) in both the second and seventh (2010–2012) waves. Fasting venous blood samples were collected in the morning, and serum DHA and EPA levels were measured. Multiple logistic regression analysis was performed among participants with an MMSE score ⩾24 in the second wave (n=430) to estimate the odds ratio (OR) and 95% confidence interval (CI) for MMSE score ⩽23 or MMSE score decline ⩾4 10 years later. These estimates were based on baseline tertiles of serum DHA or EPA levels, and controlled for age, sex, education, MMSE score at baseline, alcohol consumption, current smoking, body mass index and disease history.Results:Fifteen (3.5%) subjects whose MMSE score was ⩽23 and 36 (8.3%) subjects whose MMSE score declined to ⩾4 showed cognitive decline. Multivariate-adjusted OR (95% CI) for the lowest through highest tertiles of serum DHA to MMSE score ⩽23 or decline⩾4 were 1.00 (reference), 0.11 (0.02–0.58) and 0.17 (0.04–0.74), or 1.00 (reference), 0.22 (0.08–0.61) and 0.31 (0.12–0.75), respectively (P for trend=0.01 or 0.04). Serum EPA was not associated with cognitive decline.Conclusions:The study gives some indication that a moderately high level of serum DHA might prevent cognitive decline among community-dwelling elderly Japanese individuals.