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BACKGROUND: The etiology of prostate cancer (PCa) is not well-known, and the role of diet is not well established. We aimed to evaluate the role of the inflammatory power of the diet, measured by the Dietary Inflammatory Index (DII (R)), on the risk of PCa. METHODOLOGY: A population-based multicase-control (MCC-Spain) study was conducted. Information was collected on sociodemographic characteristics, personal and family antecedents, and lifestyles, including diet from a Food Frequency Questionnaire. The inflammatory potential of the diet was assessed using the energy-adjusted Dietary Inflammatory Index (E-DII) based on 30 parameters (a higher score indicates a higher inflammatory capacity of the diet). Tertiles of E-DII were created using the cut-off points from the control group. The International Society of Urology Pathology (ISUP) was grouped as ISUP 1, ISUP 2, or ISUP 3-5. Unconditional logistic regression models were used to estimate adjusted odds ratios (aOR) and 95% confidence intervals (CI) for the association between E-DII score and PCa risk. RESULTS: A total of 928 PCa cases and 1278 population controls were included. Among PCa cases, the mean value of the E-DII score was 0.18 (SD: 1.9) vs. 0.07 (SD: 1.9) in the control group (p = 0.162). Cases with a more pro-inflammatory diet (3rd tertile) had the highest risk of PCa, aOR(T3vsT1) = 1.30 (95% CI 1.03-1.65) (p-trend = 0.026). When stratifying by ISUP, this risk association was observed only for ISUP 2 and ISUP 3-5, aOR(T3vsT1) = 1.46 (95% CI 1.02-2.10) and 1.60 (95% CI 1.10-2.34), respectively. CONCLUSION: A positive association was observed between consuming a pro-inflammatory diet and PCa in the MCC-Spain population, specifically for an ISUP grade greater or equal than 2.