Purpose <p>This study evaluated the therapeutic benefits of combination therapy with irbesartan (an angiotensin II receptor blocker) and perindopril (an angiotensin-converting enzyme inhibitor) in experimental models of hypertension and cardiovascular injury.</p> Methods <p>Antihypertensive efficacy was assessed in spontaneously hypertensive rats (SHRs) by continuous telemetry monitoring of systolic blood pressure (SBP), mean arterial pressure (MAP), and heart rate (HR). To evaluate cardiovascular protection, myocardial ischemia/reperfusion (MI/R) was induced in SHRs by coronary artery ligation, and neointimal hyperplasia was induced in C57BL/6 mice by femoral artery cuff placement. Protective effects of the drug combination were quantified in each injury model.</p> Results <p>Co-administration of low doses of both drugs (one-quarter of each high dose) produced BP lowering comparable to that achieved with high-dose monotherapy, without affecting HR. In the MI/R model, high-dose perindopril alone and high-dose combination therapy significantly reduced the infarct zone-to-area at risk (IZ/AAR) ratio in the left ventricle, and increased endothelial nitric oxide synthase (eNOS) expression in occluded vascular tissue. In the cuff-induced vascular injury model, high-dose irbesartan or perindopril reduced neointimal thickness and the BrdU index, and high-dose combination therapy significantly reduced the BrdU index. Perindopril alone and combination therapy also reduced the BrdU index in the medial layer.</p> Conclusion <p>These findings suggest that combined irbesartan and perindopril therapy may be an effective strategy for treating hypertension and reducing associated cardiovascular complications.</p>