Background: Endoscopic sleeve gastroplasty (ESG) is an endolumenal, organ-sparing therapy for obesity, with wide global adoption. We aimed to explore the efficacy and safety of ESG with lifestyle modifications compared with lifestyle modifications alone., Methods: We conducted a randomised clinical trial at nine US centres, enrolling individuals aged 21-65 years with class 1 or class 2 obesity and who agreed to comply with lifelong dietary restrictions. Participants were randomly assigned (1:1·5; with stratified permuted blocks) to ESG with lifestyle modifications (ESG group) or lifestyle modifications alone (control group), with potential retightening or crossover to ESG, respectively, at 52 weeks. Lifestyle modifications included a low-calorie diet and physical activity. Participants in the primary ESG group were followed up for 104 weeks. The primary endpoint at 52 weeks was the percentage of excess weight loss (EWL), with excess weight being that over the ideal weight for a BMI of 25 kg/m 2 . Secondary endpoints included change in metabolic comorbidities between the groups. We used multiple imputed intention-to-treat analyses with mixed-effects models. Our analyses were done on a per-protocol basis and a modified intention-to-treat basis. The safety population was defined as all participants who underwent ESG (both primary and crossover ESG) up to 52 weeks., Findings: Between Dec 20, 2017, and June 14, 2019, 209 participants were randomly assigned to ESG (n=85) or to control (n=124). At 52 weeks, the primary endpoint of mean percentage of EWL was 49·2% (SD 32·0) for the ESG group and 3·2% (18·6) for the control group (p<0·0001). Mean percentage of total bodyweight loss was 13·6% (8·0) for the ESG group and 0·8% (5·0) for the control group (p<0·0001), and 59 (77%) of 77 participants in the ESG group reached 25% or more of EWL at 52 weeks compared with 13 (12%) of 110 in the control group (p<0·0001). At 52 weeks, 41 (80%) of 51 participants in the ESG group had an improvement in one or more metabolic comorbidities, whereas six (12%) worsened, compared with the control group in which 28 (45%) of 62 participants had similar improvement, whereas 31 (50%) worsened. At 104 weeks, 41 (68%) of 60 participants in the ESG group maintained 25% or more of EWL. ESG-related serious adverse events occurred in three (2%) of 131 participants, without mortality or need for intensive care or surgery., Interpretation: ESG is a safe intervention that resulted in significant weight loss, maintained at 104 weeks, with important improvements in metabolic comorbidities. ESG should be considered as a synergistic weight loss intervention for patients with class 1 or class 2 obesity. This trial is registered with ClinicalTrials.gov, NCT03406975., Funding: Apollo Endosurgery, Mayo Clinic., Competing Interests: Declaration of interests BKAD reports a consultant role for Endogenex, Endo-TAGSS, Metamodix, and BFKW; a consultant role and grants or research support from USGI, Spatz Medical, and Boston Scientific; speaker roles for Olympus and Johnson and Johnson; speaker fees and grant or research support from Medtronic and Endogastric Solutions; and research support from Apollo Endosurgery, Cairn Diagnostics, and Aspire Bariatrics. EBW reports grants or research support from Apollo Endosurgery and Activ Surgical; and honoraria from Intuitive, Covidien, Johnson & Johnson, and Gore Medical. RZS reports a consultant role and research support from Boston Scientific, Cook Medical, Olympus, and Lumendi. EJV reports unpaid leadership roles in the American Gastroenterological Association Trainee and Early Career Committee and American College of Gastroenterology and US Food and Drug Administration Related Matters Committee. CCT reports a consultant role for Apollo Endosurgery, Boston Scientific, Enterasense, EnVision Endoscopy, Fractyl, USGI Medical, Medtronic/Covidien, Olympus/Spiration, and GI Dynamics; being an advisory board member for USGI Medical and Fractyl; having received research grant and support from USGI Medical, Apollo Endosurgery, Boston Scientific, ERBE, FujiFilm, Lumendi Olympus/Spiration, Aspire Bariatrics, and GI Dynamics; having served as a general partner for Blueframe Healthcare; having served as a founder for Enterasense, EnVision Endoscopy, and GI Windows; and holding stock and royalties for GI Windows. CGC reports a consultant role for Boston Scientific, Apollo Endosurgery, and Olympus Corporation; a speaker role for Apollo Endosurgery, AbbVie, Boston Scientific, and Olympus; support for attending meetings from Boston Scientific, Apollo Endosurgery, and AbbVie; being a data safety and monitoring board (DSMB) member for BFKW, ERBE, and Nitinotes Surgical. VK reports a consultant role for ERBE, Apollo Endosurgery, Boston Scientific, FujiFilm, and Medtronic. MBU reports a consultant role for Boston Scientific, Cook, and Olympus; a speaker role for Apollo Endosurgery, Gore, Medtronic, and ERBE; and grants from Boston Scientific, Gore, and Medtronic. ACS reports research grant support from Apollo Endosurgery, Boston Scientific, Endogenex, Endo-TAGSS, and Enterasense; and a consultant role for Apollo Endosurgery, Boston Scientific, ERBE Elektromedizin, GI Dynamics, Intuitive Surgical, and Olympus. AJA reports a consultant role for Rhythm Pharmaceuticals, General Mills, and Amgen Pharmaceuticals; and holding shares of Gila Therapeutics and Phenomix Sciences. MM reports grants from Nestle, VectivBio, Zealand, Fresnius Kabi, and Realfood Blends; a consultant role for Baxter; being a DSMB member for EndoBarrier; and a leadership role at Oley Foundation. PJ reports a consultant role for Apollo Endosurgery, Spatz Medical, ERBS, and GI Dynamics; support for attending meetings from Endogastric Solutions; being a DSMB member for Spatz Medical; grants from Boston Scientific and ASGE; and a financial interest in USGI Medical, GI Dynamics, and Fractyl. NSB, TDW, and NZ were members of the DSMB for this study. ARR and CLK provided administrative assistance to the DSMB. CLK reports a leadership role in the American Society of Metabolic and Bariatric Surgery (ASMBS) Advance Practice Providers Committee, a role as co-chair of the ASMBS Programs Committee, and a vice president role with the Texas Association of Bariatric Surgery–Integrated Health. LE received research grant support from Mayo Clinic and is a consultant for Apollo Endosurgery. JA received research grant support from Mayo Clinic and was a consultant for Apollo Endosurgery at the time of the study; currently, JA is employed by Apollo Endosurgery as Senior Director, Global Clinical Affairs. MGN reports a consultant role for Apollo EndoSurgery, GI Dynamics, Keyron, and USGI; and a speaker role with Erbe. NZ was the DSMB chair for this study, and reports a consultant role for Ethicon, Medtronic, Olympus, GI Windows, Apollo Endosurgery, Boheringer, and LivsMed. DB, FB, BCT, AFT, OG, TK, MMC, CD, and KG declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)