PURPOSE: This study examines whether adherence to the Mediterranean Diet (MD) measured by several dietary indexes was associated with incident depressive symptoms in a large French cohort. METHODS: The study sample consisted of 3523 participants from the Supplémentation en Vitamines et Minéraux Antioxydants (SU.VI.MAX) cohort who had at least three dietary records at baseline during the first 2 years of follow-up (1994-1996), free of depression at the beginning of the study (1996-1997) and available Center for Epidemiologic Studies Depression Scale (CES-D) data at the end of follow-up (2007-2009). The rMED was computed. Incident depressive symptoms were defined by a CES-D score ≥17 for men and ≥23 for women in 2007-2009. Odds ratios (OR) and 95% confidence intervals (95% CI) were estimated using multivariable logistic regression models. Several sensitivity analyses were performed. RESULTS: In the present study, 172 incident cases of depressive symptoms were identified during the follow-up (mean = 12.6 years). After adjustment for a wide range of potential confounders, adherence to the rMED score (continuous variable) was significantly associated with incident depressive symptoms in men (OR 0.91; 95% CI 0.83-0.99; p = 0.03), but not in women. Use of the Literature-Based Adherence Score to the Mediterranean Diet (LAMD) and the classic MD score (MDS) provide similar findings. CONCLUSIONS: In the current study, higher adherence to the Mediterranean Diet at midlife was associated with a lower risk of incident depressive symptoms, particularly in men, increasing scientific evidence for a beneficial role of Mediterranean Diet on health. Further investigations in particular among women are needed.