BACKGROUND: Bariatric surgery (BS) is currently the most effective long-term treatment of severe obesity. However, the interindividual variability observed in surgical outcomes suggests a moderating effect of several factors, including individual genetic background. This study aimed to investigate the contribution of the genetic architecture of body mass index (BMI) to the variability in weight loss outcomes after BS. METHODS: A total of 106 patients with severe obesity who underwent Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy were followed up for 5 years. Changes in BMI (BMIchange) and percentage of total weight loss (%TWL) were evaluated during the postoperative period. Polygenic risk scores (PRSs), including 50 genetic variants, were calculated for each participant to determine their genetic risk of high BMI based on a previous genome-wide association study. Generalized estimating equation models were used to study the role of the individual's polygenic score and other factors on BMIchange and %TWL in the long term after surgery. RESULTS: This study found an effect of the polygenic score on %TWL and BMIchange, in which patients with lower scores had better outcomes after surgery than those with higher scores. Furthermore, when analyzing only patients who underwent RYGB, the results were replicated, showing greater weight loss after surgery for patients with lower polygenic scores. DISCUSSION: Our results indicate that genetic background assessed with PRSs, along with other individual factors, such as biological sex, age, and preoperative BMI, has an effect on BS outcomes and could represent a useful tool for estimating surgical outcomes in advance.