BACKGROUND. Roux-en-Y gastric bypass (RYGB) surgery causes profound weight loss and improves insulin sensitivity (51) in obese patients. Regular exercise can also improves S-1 in obese individuals; however, it is unknown whether exercise and RYGB surgery-induced weight loss would additively improve S-1 and other cardiometabolic factors. METHODS. We conducted a single-blind, prospective, randomized trial with 128 men and women who recently underwent RYGB surgery (within 1-3 months). Participants were randomized to either a 6-month semi-supervised moderate exercise protocol (EX, n = 66) or a health education control (CON; n = 62) intervention. Main outcomes measured included Si and glucose effectiveness (S-G), which were determined from an intravenous glucose tolerance test and minimal modeling. Secondary outcomes measured were cardiorespiratory fitness (VO2 peak) and body composition. Data were analyzed using an intention-to-treat (ITT) and per-protocol (PP) approach to assess the efficacy of the exercise intervention (>120 min of exercise/week). RESULTS. 119 (93%) participants completed the interventions, 95% for CON and 91% for EX. There was a significant decrease in body weight and fat mass for both groups.(P < 0.001 for time effect). S-1 improved in both groups following the intervention (ITT: CON vs. EX; +1.64 vs. +2.24 min(-1)/mu U/ml, P = 0.18 for Delta, P < 0.001 for time effect). A PP analysis revealed that exercise produced an additive S, improvement (PP: CON vs. EX; +1.57 vs. +2.69min(-1)/mu U/ml, P = 0.019) above that of surgery. Exercise also improved S-G (ITT: CON vs. EX; +0.0023 vs. +0.0063 min(-1), P = 0.009) compared with the CON group. Exercise improved cardiorespiratory fitness (VO2 peak) compared with the CON group. CONCLUSION. Moderate exercise following RYGB surgery provides additional improvements in S-1, S-G, and cardiorespiratory fitness compared with a sedentary lifestyle during similar weight loss.