This open-label, randomized study evaluated the effects of steady-state diltiazem on the pharmacokinetic, safety, and tolerability profile of a single dose of the novel renin inhibitor ACT-077825. Twelve healthy Caucasian male subjects (20–50 years) received in treatment sequence A, a single dose of 100 mg ACT-077825 (Days 1 and 17), and oral diltiazem 300 mg once daily (Days 14–26). In treatment sequence B, subjects received a single dose of 100 mg ACT-077825 (Days 4 and 22) and oral diltiazem 300 mg once daily (Days 1–13). ACT-077825 alone and combined with diltiazem was generally well tolerated. On average, the systemic exposure to ACT-077825 was higher in the presence of diltiazem. For AUC0–∞ and t1/2, the upper limit of the 90% confidence interval (CI) of the geometric mean ratios was outside the study-specific 0.5–2.0 equivalence boundaries, that is, 1.92 (90% CI: 1.30, 2.83) and 1.58 (90% CI: 1.22, 2.04), respectively. In conclusion, diltiazem markedly affected the pharmacokinetics of ACT-077825, probably via inhibition of CYP3A4 activity, without changing its safety and tolerability profile in healthy male subjects. Whether such an interaction will require for therapeutic dose adjustment of ACT-077825 co-administered with diltiazem has to be assessed once the dose-response relationship of ACT-077825 in hypertensive patients is determined.