PURPOSEDespite the introduction of various pharmaceutical therapies for treating obesity, selecting the optimal treatment remains challenging for both patients and physicians. Therefore, in this network meta-analysis (NMA), we aim to simultaneously compare the available drugs for treating obesity to determine the most effective treatment options.METHODSInternational databases, including PubMed, Web of Science, Scopus, Cochrane Library, and Embase, were searched for studies published from database inception to April 2023. The consistency assumption was evaluated using by the loop-specific and design × treatment interaction approaches. The effects of treatment in the NMA were summarized using mean differences based on a change score analysis. The random-effects model was used to report the results. Results were reported with 95% CIs.FINDINGSOf 9519 retrieved references, 96 randomized controlled trials, including 68 with both men and women, 23 with women only, and 5 with men only, met the eligibility criteria for this study. There were 4 treatment networks in the trials of both men and women, 4 in the trials of women only, and 1 in the trials of men only. The best-ranked treatments in the network in the trials of both men and women were (1) semaglutide, 2.4 mg (P-score = 0.99); (2) hydroxycitric acid, 4667 mg 3 times daily, supervised walking, and 2000-kcal/d diet (P-score = 0.92); (3) phentermine hydrochloride and behavioral therapy (P-score = 0.92); and (4) liraglutide plus advice to diet and exercise (P-score = 1.00). In women, the best-ranked treatments were beloranib (P-score = 0.98) and sibutramine, metformin, and hypocaloric diet (P-score = 0.90). In men, there was no significant difference among treatments.IMPLICATIONSAccording to the results of this NMA, semaglutide seems to be an effective treatment option for both men and women, whereas beloranib appears to be particularly effective for women with obesity and overweight, but its production has been stopped since 2016 and is not available.