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We examined the independent and combined effects of body mass index/obesity and diabetes mellitus in relation to the NCCN prostate cancer (PCa) risk groups in a racially-diverse cohort of men from an urban medical center. We found that obesity and diabetes were associated with high-risk PCa; however, most of the association was driven by obesity. Introduction: Obesity and diabetes mellitus (DM) have been associated with prostate cancer (PCa) risk, but data examining their combined effects on aggressive PCa are sparse, particularly among non-Hispanic Black and Hispanic men. We investigated the associations of obesity and DM in relation to National Comprehensive Cancer Network (NCCN) PCa risk groups in a racially-diverse patient population. Patients and Methods: We abstracted demographic and clinical data from men who underwent radical prostatectomy at our institution between 2005 and 2019. Patients were classified into three NCCN PCa risk-groups: low, intermediate and high-risk. Logistic regression models were used to examine the independent and combined associations of body mass index (BMI)/obesity and DM with risks of intermediate and high-risk PCa, adjusting for age and race/ethnicity. Results: A total of 1303 men with PCa (average age 60 ± 6.9 years) were analyzed. The majority were non-Hispanic Black (N = 493, 38%) or Hispanic (N = 407, 31%). The prevalence of obesity (BMI = 30 kg/m 2) and DM was 29.3% (N = 382) and 28.3% (N = 369), respectively. In multivariate analyses, obesity was independently associated with an odds ratio (OR) = 2.21 of high-risk PCa (95% CI: 1.28-3.81), while DM was associated with an OR = 1.49 (95% CI: 1.05-2.11) of intermediate-risk PCa. Compared to non-obese men without diabetes, men with BMI = 30 and DM had increased risks of both intermediate (OR = 1.93; 95% CI 1.12-3.43) and high-risk PCa (OR = 2.40; 95% CI 1.22-4.73). Interestingly, most of the association of highrisk PCa was driven by obesity. Conclusion: In this multiethnic population both obesity and DM were independently associated with intermediate- and high-risk PCa; however, most of the association for high-risk cancer was driven by obesity. Our results corroborate findings that obesity increases the risk of aggressive PCa; however, results regarding DM need to be confirmed in other large multiethnic populations. [ABSTRACT FROM AUTHOR]