Background: Bariatric surgery is an effective treatment for obesity and its associated comorbidities. This is the first comprehensive report of a prospective cohort study, comparing sleeve gastrectomy (SG) with gastric bypass (GB) regarding their effectiveness and safety. Methods: The prospectively collected data of patients, who presented to a specialized bariatric center and underwent a primary bariatric procedure, were compared in terms of weight loss, remission of obesity-associated comorbidities, complication rate, and quality of life improvement at 6-, 12-, and 24-month follow-ups. Results: Of 3287 patients (78.6% female) analyzed, 67% (n = 2202) and 33% (n = 1085) underwent SG and GB, respectively. Effective outcomes were reported in both groups regarding the body composition indices. Type 2 diabetes mellitus (T2DM) remission rate at the end of follow-up was 53.3% and 63.8% in the SG and GB groups, respectively. Following the propensity score-adjusted analysis, the T2DM remission rate was not significantly different between the groups. Conversely, the remission rate of hypertension in the 24-month follow-up (39.1% vs. 54.7%) and the remission rate of dyslipidemia in all follow-ups were lower in the SG group, compared to the GB group. Moreover, both procedures caused substantial improvements in various domains of quality of life. The surgery duration, early complication rate, and nutritional deficiencies were lower in the SG group, compared to the GB group. Conclusion: Both surgical procedures were effective in the control of obesity and remission of its comorbidities. However, since SG was associated with a lower rate of complications, it seems that SG should be considered as a suitable procedure for obese patients, especially those with a healthier metabolic profile.