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Background: World-wide the prevalence of obesity is high, and promoting a shift toward more healthful and more plant-based dietary patterns appears to be one promising strategy to address this issue. A dietary score to assess adherence to a healthy plant-based diet is the healthful plant-based diet index. While there is evidence from cohort studies that an increased healthful plant-based diet index is associated with improved risk markers, evidence from intervention studies is still lacking. Methods: A lifestyle intervention was conducted with mostly middle-aged and elderly participants from the general population (n = 115). The intervention consisted of a 16-month lifestyle program focusing on a healthy plant-based diet, physical activity, stress management, and community support. Results: After 10 weeks, significant improvements were seen in dietary quality, body weight, body mass index, waist circumference, total cholesterol, measured and calculated low-density lipoprotein (LDL) cholesterol, oxidized LDL particles, non-high-density lipoprotein cholesterol, remnant cholesterol, glucose, insulin, blood pressure, and pulse pressure. After 16 months, significant decreases were seen in body weight (−1.8 kg), body mass index (−0.6 kg/m2), and measured LDL cholesterol (−12 mg/dl). Increases in the healthful plant-based diet index were associated with risk marker improvements. Conclusions: The recommendation of moving toward a plant-based diet appears acceptable and actionable and may improve body weight. The healthful plant-based diet index can be a useful parameter for intervention studies.