IMPORTANCE: Modest weight loss can lead to meaningful risk reduction in adults with obesity. Although both behavioral economic incentives and environmental change strategies have shown promise for initial weight loss, to date they have not been combined, or compared, in a randomized clinical trial. OBJECTIVE: To test the relative effectiveness of financial incentives and environmental strategies, alone and in combination, on initial weight loss and maintenance of weight loss in adults with obesity. DESIGN, SETTING, AND PARTICIPANTS: This randomized clinical trial was conducted from 2015 to 2019 at 3 large employers in Philadelphia, Pennsylvania. A 2-by-2 factorial design was used to compare the effects of lottery-based financial incentives, environmental strategies, and their combination vs usual care on weight loss and maintenance. Interventions were delivered via website, text messages, and social media. Participants included adult employees with a body mass index (BMI; weight in kilograms divided by height in meters squared) of 30 to 55 and at least 1 other cardiovascular risk factor. Data analysis was performed from June to July 2021. INTERVENTIONS: Interventions included lottery-based financial incentives based on meeting weight loss goals, environmental change strategies tailored for individuals and delivered by text messages and social media, and combined incentives and environmental strategies. MAIN OUTCOME AND MEASURES: The primary outcome was weight change from baseline to 18 months, measured in person. RESULTS: A total of 344 participants were enrolled, with 86 participants each randomized to the financial incentives group, environmental strategies group, combined financial incentives and environmental strategies group, and usual care (control) group. Participants had a mean (SD) age of 45.6 (10.5) years and a mean (SD) BMI of 36.5 (7.1); 247 participants (71.8%) were women, 172 (50.0%) were Black, and 138 (40.1%) were White. At the primary end point of 18 months, participants in the incentives group lost a mean of 5.4 lb (95% CI, -11.3 to 0.5 lb [mean, 2.45 kg; 95% CI, -5.09 to 0.23 kg]), those in the environmental strategies group lost a mean of a 2.2 lb (95% CI, -7.7 to 3.3 lb [mean, 1.00 kg; 95% CI, -3.47 to 1.49 kg]), and the combination group lost a mean of 2.4 lb (95% CI, -8.2 to 3.3 lb [mean, 1.09 kg; 95% CI, -3.69 to 1.49 kg]) more than participants in the usual care group. Financial incentives, environmental change strategies, and their combination were not significantly more effective than usual care. At 24 months, after 6 months without an intervention, the difference in the change from baseline was similar to the 18-month results, with no significant differences among groups. CONCLUSIONS AND RELEVANCE: In this randomized clinical trial, across all study groups, participants lost a modest amount of weight but those who received financial incentives, environmental change, or the combined intervention did not lose significantly more weight than those in the usual care group. Employees with obesity may benefit from more intensive individualized weight loss strategies. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02878343.