Background and Objectives: Roux-en-Y gastric bypass (RYGB) is one of the most commonly performed metabolic and bariatric surgeries worldwide. Marginal ulcers (MU) are a common complication following RYGB, yet their pathophysiology and the contributing risk factors to their development are not fully understood. Materials and Methods: This retrospective cohort study examined patients who underwent RYGB between January 2008 and December 2023, with 1 to 5 years of follow-up. Data collected included patient- and procedure-related risk factors, as well as postoperative MU events. Statistical analysis methods included the independent samples t-tests, multivariate regression, and Cox regression analyses. Results: Our final cohort included 2106 patients and was predominantly female (80.5%), with a mean age of 47.8 ± 12.1 years and body mass index (BMI) of 45.5 ± 7.5 kg/m². MU occurred in 241 (11.4%) patients, with a mean time to occurrence of 4.5 ± 0.02 years. History of smoking (HR = 1.87, p < 0.001) and gastroesophageal reflux disease (HR = 2.36, p < 0.001) significantly increased hazard for MU, while proton pump inhibitor use (HR = 0.18, p < 0.001) was associated with reduced hazard. Aspirin exposure, regardless of dose and chronicity, did not impact MU. Conclusions: Our findings highlight the importance of preoperative assessment and counseling in patients planning to undergo RYGB. Patient-related factors should guide postoperative monitoring and prophylaxis of MU, as this remains a debated topic amongst experts.