Recent evidence demonstrates that increased adherence to the Mediterranean diet (MD) may prevent colorectal cancer (CRC). The aim of this study was to evaluate the association between health-related characteristics and CRC in the context of the MD. This was a case-control study conducted on a sample of 338 consecutive patients with a first diagnosis of CRC recruited in an urban facility in the city of Catania, southern Italy, and matched with 676 apparently healthy subjects without clinical symptoms or signs of any type of cancer. Data regarding sociodemographic, clinical, and lifestyle characteristics were collected, and adherence to the Mediterranean diet pattern was assessed using the MedDietScore. A significant association between a greater adherence to the MD and lower odds of having cancer (odds ratio = 0.46, 95% confidence interval: 0.28-0.75) was found. Also, smoking status, family history of CRC, obesity, diabetes, physical activity, and high intake of alcohol were significantly associated with CRC, but only among subjects less adherent to the MD. MD was associated with a less detrimental effects of several health-related characteristics associated with CRC, suggesting potential benefits of adherence to this dietary pattern with regards to CRC risk factors.