Objective: Evidence suggests that both Mediterranean and vegan diets improve body weight and cardiometabolic risk factors, but their relative efficacy has not been compared in a randomized trial. Methods: In a randomized crossover trial, 62 overweight adults were randomly assigned to a Mediterranean or vegan diet for a 16-week period. Body weight, plasma lipids, blood pressure, and body composition (dual X-ray absorptiometry) were measured. Secondary measures included insulin resistance (Homeostasis Model Assessment, HOMA-IR), oral glucose insulin sensitivity (OGIS), and predicted insulin sensitivity (PREDIM) indices. Thereafter, participants were asked to return to their baseline diets for 4 weeks, after which they began the opposite diet for 16 weeks. The same parameters were measured before and after this 2 nd 16-week period. Results: Overall net weight changes were 0.0 (Mediterranean) and À6.0 kg (vegan), (treatment effect À6.0 kg [95% CI À7.5 to À4.5]; p < 0.001). HOMA-IR decreased and OGIS increased on the vegan diet with no significant change on the Mediterranean diet (treatment effect À0.7 [95% CI, À1.8 to þ0.4]; p ¼ 0.21; and þ35.8 mL/min/m 2 [95% CI, þ13.2 to þ58.3]; p ¼ 0.003, respectively). PREDIM did not change significantly in either group. Among participants with no medication changes, total and LDL-cholesterol decreased 18.7 mg/dL (0.5 mmol/L) and 15.3 mg/dL (0.4 mmol/ L), respectively, on the vegan diet, compared with no significant change on the Mediterranean diet (treatment effect À15.6 [-24.6 to À6.6]; p ¼ 0.001 and À14.8 [-23.5 to À6.2]; p ¼ 0.001, respectively); systolic and diastolic blood pressure decreased 9.3 and 7.3 mmHg on the Mediterranean diet, compared with 3.4 and 4.1 mmHg on the vegan diet (treatment effect þ5.9 [95% CI þ1.0 to þ10.9]; p ¼ 0.02; and þ1.8 [95% CI À4.6 to þ8.1]; p ¼ 0.58, respectively). Conclusions: A low-fat vegan diet improved body weight, lipid concentrations, and insulin sensitivity, both from baseline and compared with a Mediterranean diet. Blood pressure decreased on both diets, more on the Mediterranean diet. Clinical trial registration: ClinicalTrials.gov number, NCT03698955 https://clinicaltrials.gov/ct2/show/NCT03698955?term=NCT03698955&draw=2&rank=1