Purpose <p>This retrospective cohort study aims to compare outcomes of Roux-en-Y gastric bypass (RYGB) versus semaglutide for treatment of recurrent weight gain (RWG) and suboptimal weight loss (SWL) after sleeve gastrectomy (SG).</p> Methods <p>Patients at a tertiary care hospital who underwent RYGB conversion after SG (<i>n</i> = 87) were matched 1:1 to SG patients treated with semaglutide (<i>n</i> = 87) by: age, gender, race, ethnicity, pre-SG to pre-intervention total weight loss (%TWL), BMI, diabetes status, and time between SG and intervention. Semaglutide ‘responders’ (defined as ≥ 5% TWL at three months, <i>n</i> = 26) and non-responders were similarly compared to the overall RYGB cohort. Weight, comorbidity, and complication outcomes were collected for two years post-intervention.</p> Results <p>%TWL two years post-intervention was greater in the RYGB compared to the semaglutide cohort (17.1% vs. 7.6%, mean difference = 9.5%, 95% CI [2.6, 16.4], <i>p</i> = 0.002), as was the proportion of patients who achieved &gt; 10% TWL (82.6% v. 40.9%, p &lt; 0.001). Diabetes medications (<i>p</i> = 0.018) and mean HbA_1c (<i>p</i> = 0.006) decreased significantly in the RYGB but not semaglutide cohort. RYGB patients had increased frequencies of GI surgeries and endoscopies. For semaglutide ‘responders,’ two-year %TWL was similar to RYGB (22.9% vs. 17.1%, <i>p</i> = 0.423).</p> Conclusions <p>RYGB led to greater and more consistent weight loss and diabetes control than semaglutide in SG patients with RWG, at the cost of an increased need for GI interventions. While only a minority of patients responded to semaglutide, these patients had similar two-year weight outcomes as RYGB.</p>