Background Obesity is prevalent in PR and has been associated with prostate cancer (PCa) mortality and aggressiveness. Polymorphisms (SNPs) rs9930506 and rs9939609 in the FTO gene have been associated with both obesity and PCa. The aim of this work was to ascertain whether the presence of these SNPs is associated with PCa risk and severity in a cohort of Puerto Rican men. Methods and findings The study population consisted of 513 Puerto Rican men age ranging from 40–79 years old who underwent radical prostatectomy (RP) as the first treatment for PCa and 128 healthy Puerto Rican men age ranging from 40–79 years old. Genomic DNA (gDNA) was extracted and SNPs were determined by Real-Time PCR. PCa severity was defined based on RP stage and Gleason Score. The relationship of FTO SNPs with demographic, clinical characteristics, PCa status and PCa severity were assessed. Logistic regression models with a 95% confidence interval (CI) determined SNPs interaction with PCa risk and severity odds ratio (ORs). Results and discussion BMI, age and PSA were considered as confounders. Hardy-Weinberg equilibrium was present for both SNPs. The heterozygous forms (A/G; T/A) were the most prevalent genotypes and the frequency of alleles and genotypes for both SNPs agreed with those published in 1000 genomes. Results suggest an inverse association between the mutated rs9939609 and the risk of having PCa (OR: 0.53, 95% CI: 0.31–0.92) and a positive association with overweight (OR: 1.05, 95% CI: 0.68–1.62). Importantly, among the cases that were overweight, those with mutated rs9939609 had a greater chance of high severity PCa (OR: 1.39, 95% CI: 0.84–2.32) although these results were not statistical significant upon adjustment. Limitations of the study were the relatively small cohort and lack of access to the weight history of all our subjects. Conclusion Results offer a research line to be followed with an expanded number of subjects that may provide a better statistical significance, to unravel the high mortality rate in this population.