ImportanceMore African American individuals die from cardiovascular disease (CVD) than any other chronic disease condition. Despite this disparity, African American individuals are underrepresented in nutrition and CVD interventions.ObjectiveTo compare the effects of an entirely plant-based (vegan) or low-fat omnivorous (omni) diet on change in body weight and lipids during a 2-year intervention.Design, Setting, and ParticipantsThe Nutritious Eating With Soul (NEW Soul) study was a 2-year, randomized clinical trial conducted in 2 cohorts (2018-2020 and 2019-2021) that took place in a university teaching kitchen in Columbia, South Carolina (before March 2020), and via online videoconference sessions (after March 2020). Participants included African American adults aged 18 to 65 years with overweight or obesity (body mass index of 25.0-49.9) and without type 2 diabetes, uncontrolled thyroid disease, recent weight loss, or pregnancy. Data assessors and statisticians were blinded to study condition. Data analysis was performed from March to June 2022.InterventionsThe intervention included weekly nutrition classes for 6 months biweekly classes for 6 months, and monthly classes for 12 months. Dietary interventions either emphasized no animal product intake (vegan) or a low-fat omnivorous diet (omni). Both dietary patterns emphasized soul food cuisine (traditional African American southern foodways).Main Outcomes and MeasuresPrimary outcomes included change in body weight and lipid measures at 12 months.ResultsThere were 568 participants who completed an online screening questionnaire; 409 were excluded and 159 were randomized (77 to the vegan group and 82 to the omni group). Of the 159 participants (mean [SD] age, 48.4 [10.6] years; 126 female [79%]) who began the study, the main outcome of body weight was obtained for 121 participants (76%) at 12 months. There were no differences in outcomes between groups, including 12-month changes in weight (mean, –2.39 kg [95% CI, –3.48 to –1.30 kg] for the vegan group vs –2.03 kg [95% CI, –3.07 to –1.00 kg] for the omni group; P = .64), total cholesterol (–1.05 mg/dL [95% CI, –9.60 to 7.50 mg/dL] for the vegan group vs 1.66 mg/dL [95% CI, –7.20 to 10.50 mg/dL] for the omni group; P = .67), or low-density lipoprotein cholesterol (mean, –2.56 mg/dL [95% CI, –9.52 to 4.40 mg/dL] for the vegan group vs –0.79 mg/dL [95% CI, –7.98 to 6.40 mg/dL] for the omni group; P = .73). Weight loss at 12 months among cohort 1, whose weight was assessed in 2019 before the COVID-19 pandemic, was significantly greater than that for cohort 2, whose weight was assessed summer 2020 during COVID-19 (–3.45 kg [95% CI, –4.67 to –2.22 kg] vs –1.24 kg [95% CI, –2.24 to –0.25 kg]; P = .01).Conclusions and RelevanceIn this randomized clinical trial examining weight loss and CVD risk factor reduction among African American adults, there were no differences between the groups, and the magnitude of changes overall was small.Trial RegistrationClinicalTrials.gov Identifier: NCT03354377