Context: Obesity is a major health concern in Saudi Arabia. Uncoupling protein 2 (UCP2) seems to play a major role in the regulation of human metabolism; therefore, genetic polymorphisms in the UCP2 gene might contribute to obesity. Aim: This study aims to establish whether 45-blood pressure (BP) insertion (I)/deletion (D) polymorphisms in UCP2 are associated with moderate and/or severe obesity in a Saudi Arabian population. Settings and Design: Case–control study design. Materials and Methods: The study enrolled 151 male and female subjects originating from the eastern province of Saudi Arabia, and assigned each to a “nonobese,” “moderately obese,” or “severely obese” group. Genomic DNA was extracted from all subjects and screened for UCP2 I/D polymorphisms using a standard polymerase chain response protocol. Statistical Analysis Used: Analysis of variance, Chi-squared tests, and logistic regression analysis. Results: The frequencies of the UCP2 45-BP I/D genotypes D/D, I/D, and I/I within the analyzed population were 58.3%, 36.4%, and 5.3%, respectively. The D/D genotype was highly prevalent within the severely obese group (82.9%) compared to the nonobese (46.2%) and moderately obese (53.3%) groups. Using a dominance model, the conducted logistic regression analysis showed a strong association between the deletion allele and severe obesity (Odds ratio = 0.18, 95% confidence interval: 0.07–0.44, P = 0.0004). Conclusions: The present study reported that the frequency of UCP2 45-BP I/D polymorphisms in a population originating from eastern Saudi Arabia and identified a strong association between the D/D genotype and severe obesity.