Introduction: Trends in diet quality worldwide indicate a progressive decline in adherence to Mediterranean diet (MD), but data on longitudinal individual-level changes are still limited, especially in Mediterranean countries. Hypothesis: We assessed the hypothesis of an association, in a Mediterranean population, between life course trajectories in MD and concurrent long-term modifications of risk factors for cardiovascular disease (CVD) and inflammatory markers. Methods: We followed 2,107 men and women (mean age at baseline 54.6±8.8 y) from the Moli-sani Study (Italy) between 2005 and 2020. Dietary data were measured at baseline and at a re-examination (after an average of 12.7 years) and were collected by a 188-item food frequency questionnaire. Adherence to MD was estimated by a Mediterranean diet score based on 9 food groups, ranging from 0 to 9 points. MD trajectories were identified as downward (-6 to -2 points in MDS), relatively stable (-1 to 0) and upward (1 to 6). Inflammation was measured by both an INFLA-score including C-reactive protein and cellular markers ( e.g ., leukocyte count) and a CYTO-score including 14 selected analytes (cytokines, chemokines and growth factors). Regression models were used to examine changes in MDS, CVD risk factors and inflammation markers within the same period. Results: Overall, adherence to MD decreased by an average of 6.5% over follow-up. As opposed to the downward, an upward trajectory in MD adherence was inversely associated with the INFLA-score (β=-0.177; 95%CI -0.296, -0.058) and the CYTO-score (β=-0.311; 95%CI -0.548, -0.073). No significant changes were observed for CVD risk factors, with the exception of an increase in blood glucose (β=0.121; 95%CI 0.001, 0.241) and systolic blood pressure (β=0.110; 95%CI 0.003, 0.217) associated with an upward MD trajectory. Conclusions: In a large sample of Mediterranean individuals, diet quality, as reflected by adherence to an MD, has been declining over the last decade. However, in the group of subjects who improved their adherence to an MD, a significant reduction of markers of an inflammatory status was documented, possibly predisposing to a better duration and quality of life.