Translational lifestyle change programs for community and clinical settings have been available for a decade, yet there are limited data on their comparative effectiveness. This study examines the effectiveness of a Centers for Disease Control and Prevention-aligned lifestyle change program relative to usual care in clinical practice. This was an electronic health record-based retrospective cohort study conducted in a community-based healthcare system. Investigators identified adult program participants and usual-care patients in the electronic health record between 2010 and 2018 and defined their index date (baseline) as the first lifestyle change program encounter or a random encounter date, respectively. Participants were matched 1:2 to usual-care patients on baseline demographics and clinical characteristics using propensity-score methods. Changes in body weight and blood pressure were examined from baseline through 24 months. The authors identified 2,833 program participants and 438,432 usual-care patients meeting study eligibility criteria. A total of 2,833 program participants were matched to 4,776 usual-care patients; the average age was 54 years, and 80% of the participants were female. Program participation was associated with a 1.9- and 1.6-fold higher prevalence of clinically meaningful (≥5%) weight loss at 12- and 24-month follow-up than usual care and a higher prevalence of blood pressure control at 12 months but not at 24 months. Patients without type 2 diabetes at baseline had more pronounced outcomes than those with type 2 diabetes. This study demonstrates the effectiveness of an evidence-based, Centers for Disease Control and Prevention-aligned lifestyle change program in reducing cardiometabolic risk factors compared with usual care in clinical practice, with long-term reductions in weight and transient reductions in blood pressure.