Objective: To assess the long-term effects of a prepackaged, nutritionally complete, prepared meal plan compared with a usual-care diet (UCD) on weight loss and cardiovascular risk factors in overweight and obese persons. Design: In this randomized multicenter study, 302 persons with hypertension and dyslipidemia (n = 183) or with type 2 diabetes mellitus (n = 119) were randomized to the nutrient-fortified prepared meal plan (approximately 22% energy from fat, 58% from carbohydrate, and 20% from protein) or to a macronutrient-equivalent UCD. Main Outcome Measures: The primary outcome measure was weight change. Secondary measures were changes in blood pressure or plasma lipid, lipoprotein, glucose, or glycosylated hemoglobin levels; quality of life; nutrient intake; and dietary compliance. Results: After 1 year, weight change in the hypertension/dyslipidemia group was -5.8 ± 6.8 kg with the prepared meal plan vs -1.7 ± 6.5 kg with the UCD plan (P<.001); for the type 2 diabetes mellitus group, the change was -3.0 ± 5.4 kg with the prepared meal plan vs -1.0 ± 3.8 kg with the UCD plan (P<.001) (data given as mean ± SD). In both groups, both interventions improved blood pressure, total and low-density lipoprotein cholesterol levels, glycosylated hemoglobin level, and quality of life (P<.02); in the diabetic group, the glucose level was reduced (P<.001). Compared with those in the UCD group, participants with hypertension/dyslipidemia in the prepared meal plan group showed greater improvements in total (P<.01) and high-density lipoprotein (P<.03) cholesterol levels, systolic blood pressure (P<.03), and glucose level (P<.03); in participants with type 2 diabetes mellitus, there were greater improvements in glucose (P=.046) and glycosylated hemoglobin (P<.02) levels. The prepared meal plan group also showed greater improvements in quality of life (P<.05) and compliance (P<.001) than the UCD group. Conclusions: Long-term dietary interventions induced significant weight loss and improved cardiovascular risk in high-risk patients. The prepared meal plan simultaneously provided the simplicity and nutrient composition necessary to maintain long-term compliance and to reduce cardiovascular risk.