Prostate cancer (PCa) is the second most frequently diagnosed cancer and the sixth leading cause of death from cancer worldwide. Countries following a Mediterranean-type dietary pattern, has been reported to have lower PCa incidence and mortality compared with other European regions. A population-based case-control study has been conducted from January 2015 to December 2016 in a single institution of the municipality of Catania, southern Italy. A total of 118 PCa and 238 population-based controls were collected. Controls had significantly higher adherence to the Mediterranean diet, which was evident for several subgroups (including age groups, overweight and obese men, current smokers, alcohol intake, low and medium physical activity levels). PCa cases were found to consume lower amount of vegetables (223 g/d vs. 261 g/d; p = 0.001), legumes (34.26 g/d vs. 53.55 g/d; p = 0.003), and fish (47.75 g/d vs. 58.3 g/d) than controls; other differences emerged were related to alcohol intake (12.37 g/d vs 5.07 g/d; p < 0.01), cereals (254.06 g/d vs.235.94 g/d; p < 0.001), dairy (196 g/d vs. 166 g/d; p < 0.001), and meat consumption (98.09 g/d vs. 70.15 g/d; p < 0.001). However, no statistically significant differences between cases and controls were found regarding fruit, legumes, and olive oil consumption. The Mediterranean diet score was inversely associated with lower likelihood of having PCa in a linear manner (odds ratio [OR]: 0.86 [95% CI 0.77-0.96]). Specifically, individuals in the highest group of adherence had 78% less likelihood of have PCa and 14% less likelihood for each point increase of the score. The model adjusted for total polyphenol intake showed still a significant inverse association between adherence to the Mediterranean diet and PCa, but the relation was no more linear and not significant for one-point increase of the score (OR: 0.88 [95% CI 0.77-1.01]). In our cohorts of Italian men, we observed that high adherence to the Mediterranean diet was inversely associated with likelihood of having PCa cancer.