Abstract Objective: Hispanics have lower incidence and mortality rates of prostate cancer (PCa) than non-Hispanics whites; however, they are more likely to be diagnosed with and die from advanced stage PCa. Obesity (BMI ≥ 30 kg/m2) is positively associated with high-grade and advanced stage disease and mortality while the inverse is true for diabetes. Compared to non-Hispanic whites (NHW), little is known about the association of overweight (BMI ≥ 25 kg/m2), obesity, diabetes, and their simultaneous presence with different stages of PCa in Hispanics. The role of these independent factors and their simultaneous presence on PCa in Mexican-Americans warrants a detailed investigation as this population has a higher prevalence of overweight, physician-diagnosed diabetes, and overweight adults with diagnosed diabetes than NHW's. This understudied population is one of the fastest growing ethnic populations in the US. To the best of our knowledge, there are no studies on the relationship of overweight, diabetes and their simultaneous presence with localized and advanced PCa in Mexican-Americans. Materials and methods: We conducted a population-based case-control study in Mexican-American men residing in southeast Texas. Men diagnosed with histologically confirmed adenocarcinoma of the prostate (n=237) were included. Controls (n=245) were identified through random-digit dialing and frequency-matched to cases on age (±5 years). BMI, diabetes and hypertension were self-reported. Abdominal obesity was defined by waist circumference ≥ 102 cm. We identified overweight among men with self-reported diabetes to investigate their effect on PCa stage. Multivariate logistic regression was used to estimate independent associations between these factors with localized and advanced PCa. Results: Although none of the multivariate associations were statistically significant, the direction and strength of the observed associations were consistent with previous epidemiological studies. After adjusting for PCa risk factors (age, education, family history of PCa, physical activity, smoking, alcohol consumption, PSA screening and birth place), obesity was positively and diabetes inversely associated with localized and advanced PCa. Overweight reduced the risk of localized PCa, but increased the risk of advanced PCa. Men who were overweight with self-reported diabetes had a reduced risk for both, localized and advanced PCa. Similar results were observed for abdominal obesity. On the other hand, hypertension and being born in the US (USA vs. Mexico) consistently increased the risk for localized and advanced disease. Conclusion: High prevalence of obesity, overweight, diabetes and their simultaneous effect among Mexican-American men seem to influence PCa stage differentially. Since these factors have opposite effects on PCa, it is important to be cautious when inferring conclusions when both of them are present. It is possible that different BMI cut-off points and biological mechanisms are playing a role in these associations. Citation Information: Cancer Prev Res 2011;4(10 Suppl):B94.