The Mediterranean diet (MeDi) is known to prevent cardiovascular events but the mechanisms mediating this association are not fully understood. The objective of the study was to examine the association between MeDi adherence and the presence and extent of atherosclerotic plaques in carotid, femoral, and aorta territories and its relationship with risk factors in asymptomatic middle-aged adults. Cross-sectional analysis of the Aragon Workers' Health Study, a cohort of 2588 subjects (94.9% men aged 51.3 ± 3.89 years) without previous cardiovascular history. Participants underwent carotid, femoral, and aorta ultrasound for the quantification of number and thickness of plaques and intima-media thickness. To estimate the participant's adherence to MeDi, we computed the Alternative MEDiterranean index (aMED). The overall aMED score was 4.19 ± 1.70, representing a moderate adherence to MeDi. aMED score was associated with the presence of plaque in femoral arteries (odds ratio highest vs lowest aMED score quartile: 0.63; 95% confidence interval: 0.48–0.83; P trend = .045) independently of risk factors and mediators. The strongest association between aMED quartiles and presence of plaque was found among smokers, both in femoral (0.39 0.22–0.69; P trend = .001) and in any territory (0.33 0.14–0.79, P trend = .008). aMED was inversely associated with the number of plaques in all territories except for carotids. MeDi adherence showed a dose-dependent protective association with the presence, number, and thickness of plaques independent of other risk factors. The association was strongest for femoral arteries and among smokers. •This is the first study of MEDiterranean (MeDi) and atherosclerosis in different territories.•MeDi adherence is directly correlated to presence of plaque mainly in femoral.•MeDi induces the highest protection against plaque presence in smokers.•Mediterranean diet adherence was dose dependently related to number of plaques.•Protective effect of diet on atherosclerosis was independent of risk factors.