The effect of Mediterranean diet on colorectal cancer, in the presence of the metabolic syndrome, was evaluated in 250 patients with first developed cancer (63 ± 12 years, 59% males) and 250 age-gender-matched controls. Adherence to the Mediterranean diet was evaluated with the modified-MedDietScore (theoretical range 0-75), while assessment of the metabolic syndrome (MetS) was based on the third Adult Treatment Panel ([ATP III] National Cholesterol Education Program) criteria. Presence of MetS (1.66, 95% confidence interval [CI] 1.02, 2.69), age (4.25, 95% CI 2.33, 7.77), smoking (1.85, 95% CI 1.27, 2.70), and family history of colorectal cancer (3.37, 95% CI 1.69, 6.75) had a detrimental effect, whereas adherence to the Mediterranean diet (0.88, 95% CI 0.84, 0.92) and body mass index (0.93, 95%CI 0.89, 0.98) had a protective role regarding colorectal cancer. Mediterranean diet had the same effect in relation to colorectal cancer, in both participants with (0.84, 95% CI 0.76, 0.93) and without MetS (0.89, 95% CI 0.85, 0.94).