Objectives The study sought to assess the primary preventive effect of neurohumoral therapy in high-risk diabetic patients selected by N-terminal pro–B-type natriuretic peptide (NT-proBNP). Background Few clinical trials have successfully demonstrated the prevention of cardiac events in patients with diabetes. One reason for this might be an inaccurate selection of patients. NT-proBNP has not been assessed in this context. Methods A total of 300 patients with type 2 diabetes, elevated NT-proBNP (>125 pg/ml) but free of cardiac disease were randomized. The “control” group was cared for at 4 diabetes care units; the “intensified” group was additionally treated at a cardiac outpatient clinic for the up-titration of renin-angiotensin system (RAS) antagonists and beta-blockers. The primary endpoint was hospitalization/death due to cardiac disease after 2 years. Results At baseline, the mean age of the patients was 67.5 ± 9 years, duration of diabetes was 15 ± 12 years, 37% were male, HbA1c was 7 ± 1.1%, blood pressure was 151 ± 22 mm Hg, heart rate was 72 ± 11 beats/min, median NT-proBNP was 265.5 pg/ml (interquartile range: 180.8 to 401.8 pg/ml). After 12 months there was a significant difference between the number of patients treated with a RAS antagonist/beta-blocker and the dosage reached between groups (p < 0.0001). Blood pressure was significantly reduced in both (p < 0.05); heart rate was only reduced in the intensified group (p = 0.004). A significant reduction of the primary endpoint (hazard ratio: 0.351; 95% confidence interval: 0.127 to 0.975, p = 0.044) was visible in the intensified group. The same was true for other endpoints: all-cause hospitalization, unplanned cardiovascular hospitalizations/death (p < 0.05 for all). Conclusions Accelerated up-titration of RAS antagonists and beta-blockers to maximum tolerated dosages is an effective and safe intervention for the primary prevention of cardiac events for diabetic patients pre-selected using NT-proBNP. (Nt-proBNP Guided Primary Prevention of CV Events in Diabetic Patients PONTIAC; NCT00562952 )