Randomized trials have shown significant blood pressure (BP) reductions after increased protein compared with carbohydrate intake, but the effect on BP maintenance after initial weight loss is unclear. We examined the effect of a high-protein diet on the maintenance of reduced BP after weight loss in 420 overweight adults from the Diet, Obesity and Genes study. After an 8-week weight-loss period (>8% BW), subjects (42+/-6 years) were randomized to either a high-protein diet (23-28 en% protein) or a lower-protein control diet (10-15 en% protein) for 26 weeks. BMI after weight loss was 30.3+/-4.3 kg m-2, BP was 118/73 mm Hg and 28 subjects (6.5%) used antihypertensive agents. Systolic BP during 26 weeks of weight maintenance dietary intervention increased in both treatment groups, but it was 2.2 mm Hg less (95% CI: -4.6 to 0.2 mm Hg, P=0.08) in the high-protein group than in the lower-protein control group. In 191 (pre)hypertensive subjects (baseline systolic BP120 mm Hg), a larger difference was observed (-4.2 mm Hg (-7.7, -0.7), P=0.02). The effect was attenuated after adjustment for initial BP (-3.4 mm Hg (-6.9, -0.03), P=0.048), and after additional adjustment for weight change (-2.7 mm Hg (-6.1, 0.4), P=0.11). Adjustment for 24-h urinary excretion of sodium and potassium did not change the results. Diastolic BP yielded similar results. These findings suggest that a BP reduction after weight loss is better maintained when the intake of protein is increased at the expense of carbohydrates. This effect is partly mediated by body weight.Journal of Human Hypertension advance online publication, 24 April 2014; doi:10.1038/jhh.2014.30.