Background: Western diets, which typically contain large amounts of energy-dense processed foods, together with a sedentary lifestyle are associated with increased cardiometabolic risk. We evaluated the long-term effects of consuming a low-calorie low-protein vegan diet or performing regular endurance exercise on cardiometabolic risk factors. Methods: In this cross-sectional study, cardiometabolic risk factors were evaluated in 21 sedentary subjects, who had been on a low-calorie low-protein raw vegan diet for 4.4 ± 2.8 years, (mean age, 53.1 ± 11 yrs), 21 body mass index (BMI)-matched endurance runners consuming Western diets, and 21 age-and gender-matched sedentary subjects, consuming Western diets. Results: BMI was lower in the low-calorie low-protein vegan diet (21.3 ± 3.1 kg/m2) and endurance runner (21.1 ± 1.6 kg/m2) groups than in the sedentary Western diet group (26.5 ± 2.7 kg/m2) (p < 0.005). Plasma concentrations of lipids, lipoproteins, glucose, insulin, C-reactive protein, blood pressure (BP), and carotid artery intima-media thickness were lower in the low-calorie low-protein vegan diet and runner groups than in the Western diet group (all p < 0.05). Both systolic and diastolic BP were lower in the low-calorie low-protein vegan diet group (104 ± 15 and 62 ± 11 mm Hg) than in BMI-matched endurance runners (122 ± 13 and 72 ± 9 mmHg) and Western diet group (132 ± 14 and 79 ± 8 mm Hg) (p < 0.001); BP values were directly associated with sodium intake and inversely associated with potassium and fiber intake. Conclusions: Long-term consumption of a low-calorie low-protein vegan diet or regular endurance exercise training is associated with low cardiometabolic risk. Moreover, our data suggest that specific components of a low-calorie low-protein vegan diet provide additional beneficial effects on blood pressure.