We aimed to evaluate efficacy and tolerability of a protocol including lifestyle modifications and a novel combination of dietary supplements in prehypertension. A prospective, double-blind, randomised, placebo-controlled trial was conducted in 176 subjects (103 men, aged 52 ± 10 years), with blood pressure (BP) of 130-139 mm Hg systolic and/or 85-89 mm Hg diastolic entered. After a single-blind run-in period, participants were randomised to twice daily placebo (n = 88) or a commercially available combination pill (n = 88). Primary endpoints were the differences in clinic BP between the two groups at the end of the trial. Secondary endpoints included intragroup differences in clinic BP during the study period and response rates (that is, BP < 130/85 mm Hg or a BP reduction > 5 mm Hg on week 12). Baseline characteristics were similar among the treatment groups. At 12 weeks, the supplement group had lower systolic BP (124 ± 9 versus 132 ± 7 mm Hg, P < 0.0001) and similar diastolic BP (81 ± 8 versus 82 ± 7 mm Hg, P = 0.382) compared to the placebo group. With respect to baseline measures, changes in BP with supplements were statistically significant for systolic (-9.3 ± 4.2 mm Hg, P < 0.0001) and diastolic values (-4.2 ± 3.6 mm Hg, P < 0.0001). Changes versus baseline in systolic and diastolic BP, conversely, were not different on placebo. The overall response rate at week 12 was significantly greater with supplements than placebo (58% (51 of 88) and 25% (22 of 88), respectively, P < 0.0001). This randomised trial shows that combination of supplements with BP-lowering effect is an effective additional treatment to conventional lifestyle modifications for a better control of systolic BP in prehypertension.