Importance: People with a severe mental illness (SMI) have a life expectancy reduced by 10 to 20 years compared with the general population, primarily attributable to cardiometabolic disorders. Lifestyle interventions for people with SMI can improve health and reduce cardiometabolic risk. Objective: To evaluate the effectiveness of a group-based lifestyle intervention among people with SMI in outpatient treatment settings compared with treatment as usual (TAU). Design, Setting, and Participants: The Severe Mental Illness Lifestyle Evaluation (SMILE) study is a pragmatic cluster randomized clinical trial performed in 8 mental health care centers with 21 flexible assertive community treatment teams in the Netherlands. Inclusion criteria were SMI, age of 18 years or older, and body mass index (calculated as weight in kilograms divided by height in meters squared) of 27 or greater. Data were collected from January 2018 to February 2020, and data were analyzed from September 2020 to February 2023. Interventions: Weekly 2-hour group sessions for 6 months followed by monthly 2-hour group sessions for another 6 months, delivered by trained mental health care workers. The intervention targeted overall lifestyle changes, emphasizing establishing a healthy diet and promoting physical activity. TAU (control) did not include structured interventions or advice on lifestyle. Main Outcomes and Measures: Crude and adjusted linear mixed models and multivariable logistic regression analyses were performed. The main outcome was body weight change. Secondary outcomes included changes in body mass index, blood pressure, lipid profiles, fasting glucose level, quality of life, self-management ability, and lifestyle behaviors (physical activity and health, mental health, nutrition, and sleep). Results: The study population included 11 lifestyle intervention teams (126 participants) and 10 TAU teams (98 participants). Of 224 included patients, 137 (61.2%) were female, and the mean (SD) age was 47.6 (11.1) years. From baseline to 12 months, participants in the lifestyle intervention group lost 3.3 kg (95% CI, -6.2 to -0.4) more than those in the control group. In the lifestyle intervention group, people with high attendance rates lost more weight than participants with medium and low rates (mean [SD] weight loss: high, -4.9 [8.1] kg; medium, -0.2 [7.8] kg; low, 0.8 [8.3] kg). Only small or no changes were found for secondary outcomes. Conclusions and Relevance: In this trial, the lifestyle intervention significantly reduced weight from baseline to 12 months in overweight and obese adults with SMI. Tailoring lifestyle interventions and increasing attendance rates might be beneficial for people with SMI. Trial Registration: Netherlands Trial Register Identifier: NTR6837.