BACKGROUND: The 2015-2020 Dietary Guidelines for Americans recommend a Mediterranean-type diet as one of three healthful eating patterns. However, only one previous trial has evaluated the effects of a Mediterranean diet intervention in a US sample population. METHODS: To address this gap, we conducted a pilot, non-blinded, 8-week randomized controlled trial on the comparative efficacy of consumption of a Mediterranean diet or a diet supplemented with fish oil, walnuts, and grape juice versus controls. Participants (overweight or obese US adults; 73% female and mean age 51 years) were randomly assigned to one of three groups: (1) Mediterranean diet; (2) habitual high-fat American-type diet supplemented with fish oil, walnuts, and grape juice; or (3) habitual high-fat American-type diet (controls). Intent-to-treat analysis of within-subject differences (Student's paired t-test or Wilcoxon sign ranks test) and between-subject differences (mixed-effects models with a group-by-time interaction term, adjusted for baseline health outcome) was conducted. RESULTS: Participants in the Mediterranean diet arm (n = 11) had significantly greater weight loss despite no significant change in total caloric intake, and lower plasma cystine, indicative of decreased oxidative stress, compared to controls (n = 9) at both 4 and 8 weeks. Compared to controls, they also had significantly lower total cholesterol and low-density lipoprotein cholesterol levels at 4 weeks. Participants in the supplement arm (n = 10) had significantly lower adiponectin levels compared to controls at 4 weeks. No significant improvements in endothelial function or inflammatory biomarkers were observed in either intervention group compared to controls. CONCLUSION: These results suggest that adopting a dietary pattern reflecting a Mediterranean diet improves weight and cardio-metabolic health among overweight or obese US adults, and may be more beneficial than supplementing habitual American diets with fish oil, walnuts, and grape juice.