BACKGROUND: Current guidelines call for peer-reviewed evidence of efficacy and safety for commercial weight loss programs to be recommended as options for those seeking to lose weight. OBJECTIVES: This study investigated the Ideal Protein (IP) system, a commercial weight loss program, compared to a guideline-based, low-calorie/low-fat (LCLF) dietary behavioral intervention on body weight and CVD risk factors in adults with obesity. METHODS: In this randomized, assessor-blinded, parallel-group trial, 192 participants with body mass index (BMI) ≥30 and ≤49 kg/m2 were assigned to either the IP Phase I diet or LFLC diet interventions. The IP Phase I is focused on lean protein and vegetables with avoidance of fruit and dairy, while the LFLC diet goals include <30% of daily energy from fat, <7% from saturated fat, 55% from carbohydrate, and an energy deficit of 500 kcal/day. The primary endpoint was change in body weight at 3 months. Secondary endpoints included change in waist circumference (WC), hip circumference (HC), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), fasting glucose (FG), systolic blood pressure (SBP) and diastolic blood pressure (DBP). RESULTS: The mean ± SD of change in weight at 3 months was -9.6 ± 12.7 kg in the IP group as compared to -1.6 ± 27.2 kg in the LFLC group. The mean between-group difference in change at 3 months was -8.1 kg (95% confidence interval [CI] -16.6 to 0.6; p = 0.05). Additional significant between-group differences included WC, HC, TC, and TG levels, all favoring the IP group. There were no serious adverse events during the intervention period. CONCLUSIONS: The present findings demonstrate the efficacy and safety of the IP weight loss program as compared to a guideline-based LCLF dietary behavioral intervention among black and white adults with obesity and CVD risk factors, providing support for the effectiveness of the program.