OBJECTIVES: There are no human studies assessing the effect of nutritional interventions on plasma brain-derived neurotrophic factor (BDNF) concentrations. The aim of this study was to assess the role of a nutritional intervention based on a Mediterranean diet (MeDiet) on plasma BDNF levels. METHODS: PREvención con Dieta MEDiterránea (PREDIMED) is a randomized clinical trial designed to assess the effect of a Mediterranean diet (MeDiet) on the primary prevention of cardiovascular disease. For this analysis, 243 participants from the Navarra centre were randomly selected. Participants were assigned to one of three dietary interventions: control (low-fat) diet, MeDiet supplemented with virgin olive oil (MeDiet+VOO), or MeDiet supplemented with nuts (MeDiet+Nuts). Plasma BDNF levels were measured after 3 years of intervention. Multivariate-adjusted means of BDNF for each intervention were compared using generalized linear models. Logistic regression models were fit to assess the association between the dietary intervention and the likelihood to have low plasma BDNF values (<13 µg/ml, 10th percentile). Analyses were repeated after stratifying the sample according to baseline prevalence of different diseases. RESULTS: Higher but non-significant plasma BDNF levels were observed for participants assigned to both MeDiets. Participants assigned to MeDiet+Nuts showed a significant lower risk (odds ratios (OR)=0.22; 95% confidence intervals (CI)=0.05-0.90) of low plasma BDNF values (<13 µg/ml) as compared to the control group. Among participants with prevalent depression at baseline, significantly higher BDNF levels were found for those assigned to the MeDiet+Nuts. DISCUSSION: Adherence to a MeDiet was associated to an improvement in plasma BDNF concentrations in individuals with depression.