The aim of the present study was to analyse the association between adherence to the Mediterranean diet and self-perceived mental and physical health function, controlled for confounding effects of age, smoking, BMI, alcohol consumption, educational level, leisure-time physical activity and the presence of chronic conditions. A random sample of the 35-74-year-old population (3910 men and 4285 women) of Gerona, Spain, was examined in 2000 and 2005 in two independent population-based cross-sectional surveys. Dietary intake was assessed using a validated FFQ. The Mediterranean diet score (MDS) was calculated according to tertile distribution of energy-adjusted food consumption considered characteristic for the Mediterranean region. Health-related quality of life was measured using the SF-12 questionnaire. Alcohol consumption, leisure-time physical activity and smoking habits were recorded. Weight and height were measured. Age-adjusted linear regression analysis revealed a significant (P < 0.01) direct association of the MDS with self-reported mental and physical health in both sexes. An increase of 5 units of the MDS was directly associated with changes of 0.74 and 1.15 units in men and women, respectively, in the mental component score after controlling for potential confounders. The age-adjusted direct association of the MDS with self-reported scoring of physical health remained stable after adjusting for several confounders in men but was attenuated in women. Adherence to the Mediterranean diet was associated with higher scoring for self-perceived health.